Method for treating 5-HT2B receptor related conditions

ABSTRACT

The present invention provides methods for binding a 5-HT 2B  receptor in mammals using a both known and novel compounds. Further, the invention provides a method for treating or preventing 5-HT 2B  related conditions. Finally, the invention provides an article of manufacture.

CROSS REFERENCE

This application is a division of application Ser. No. 08/380,566, filedFeb. 6, 1995, now abandoned, which is a continuation-in-part ofapplication Ser. No. 08/212,622, filed Mar. 11, 1994, which is nowabandoned.

FIELD OF THE INVENTION

The present invention relates to a method for treating 5HT_(2B) receptorrelated conditions. Further, this application discloses new compounds ofFormulas XI and XII infra.

BACKGROUND OF THE INVENTION

This invention is directed to a method for treating a mammal sufferingfrom or susceptible to a condition associated with modulation of a5-HT_(2B) receptor.

Blocking serotonin receptors has been shown to result in a number ofbeneficial pharmacological effects, including reduction in diseasestates such as hypertension, depression, anxiety, and the like; see U.S.Pat. No. 5,141,944. Nelson et al., Psychopharmacology and Biochemistryof Neurotransmitter Receptors, eds. H. I. Yamamura et al.,Elsevier/North Holland Inc., p 325, have confirmed that there aremultiple serotonin recognition sites. The general class of serotoninreceptors are referred to as the 5-HT receptors. Specific 5-HT receptorsites include 5-HT_(1A), 5-HT_(1B), 5-HT_(1D), 5-HT_(2A), 5-HT_(2B),5-HT_(2C), 5-HT₃, and 5-HT₄ sites. Each of these receptors mediatescertain physiological effects. See Leonard, B. E., InternationalClinical Psychopharmacology, 7:13-21 (1992).

This invention provides a method for using compounds which are active atthe 5-HT_(2B) receptor to treat or prevent 5-HT_(2B) related conditions.Further, this invention provides a method for selectively blocking the5-HT_(2B) receptor. Additionally, this invention provides a method forblocking human 5-HT_(2B) receptors. The 5-HT_(2B) receptor activecompounds provide a useful tool for characterizing the 5-HT_(2B)receptor.

This invention provides a group of compounds which are 5HT_(2B) receptorantagonists. Applicants have discovered that such compounds are potentcompetitive inhibitors of serotonin-induced contraction of the colon.Thus, this invention provides compounds which can act to normalizegastrointestinal motility and be useful in the treatment of FunctionalBowel Disorders.

Further, it has been discovered the 5-HT_(2B) receptor is localized inthe rat lung, stomach fundus, uterus, bladder, and colon. Interestingareas of 5-HT_(2B) receptor localization in the human include but arenot limited to the brain and blood vessels. Thus, conditions which canbe treated using a compound which modulates a 5-HT_(2B) receptorincludes, for example, psychosis, depression, anxiety disorders, uterinediseases such as endometriosis, fibrosis, and other abnormal uterinecontractivity, panic attack, migraine, eating disorders, seasonalaffective disorder, consumption disorders, cardiovascular conditions,such as thrombosis, hypertension, angina, vasospasm, and other vascularocclusive diseases, incontinence, bladder dysfunction,respiratory/airway disorders including asthma, and the like.

SUMMARY OF THE INVENTION

This invention provides a method for treating a mammal suffering from orsusceptible to a condition associated with dysfunctional or abnormal5-HT_(2B) receptor stimulation, comprising administering an effectiveamount of a compound interacting with the 5HT_(2B) receptor as anagonist, partial agonist or antagonist selected from the groupconsisting of a compound of the Formula I ##STR1## wherein: Q ishydrogen or (CHR₂)R₄

R₁ is hydrogen or C₁ -C₃ alkyl;

R₂ is hydrogen or C₁ -C₃ alkyl;

R₃ is hydrogen or C₁ -C₃ alkyl;

R₄ is C₅ -C₈ cycloalkyl, substituted C₅ -C₈ cycloalkyl, C₅ -C₈cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, bicyclic or substitutedbicyclic;

A is selected from the group consisting of ##STR2## wherein R₆ and R₇are, independently, hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, or OR₅ ;

m is 1 or 2;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₈ is independently selected from the group consisting of an R₆ group,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, C₇ -C₂₀ arylalkyl; or

R₆ and R₇ together with the carbon atoms of group A form a 5- to8-member carbon ring;,

a compound of Formula II ##STR3## wherein R₈ is selected from the groupconsisting of hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo, halo(C₂-C₆)alkyl, halo(C₁ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁-C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅, substituted C₃ -C₈ cycloalkyl, C₃-C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl,substituted C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, andC₇ -C₂₀ arylalkyl;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₉ and R₁₀ are independently selected from the group consisting ofhydrogen, C₁ -C₆ alkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁-C₃)alkyl, C₇ -C₂₀ arylalkyl;

R₁₁ is selected from the group consisting of C₁ -C₄ alkyl, OR_(5'),fluoro, bromo, iodo, and chloro;

R_(12') is selected from the group consisting of hydrogen and C₁ -C₄alkyl;

a compound of Formula III ##STR4## wherein: R¹² is C₁ -C₄ alkyl orallyl;

R¹³ is --O-- or --N(R¹⁵)--;

R¹⁵ is hydrogen or C₁ -C₄ alkyl;

R¹⁴ is C₁ -C₄ alkyl, hydroxy C₁ -C₄ alkyl, C₃ -C₇ cycloalkyl, and C₃ -C₇cycloalkyl substituted with hydroxy or methoxy;

a compound of Formula IV ##STR5## wherein: R^(15') is C₁ -C₄ alkyl;

R¹⁶ is allyl or C₁ -C₄ straight chain alkyl;

R¹⁷ is hydrogen or C₁ -C₄ straight chain alkyl;

R¹⁸ is hydrogen, C₁ -C₄ alkyl, hydroxy, or C₁ -C₄ alkyloxy;

m' is 0, 1, 2, or 3;

a compound of Formula V ##STR6## wherein: R¹⁹ is C₁ -C₄ alkyl;

R²⁰ is allyl or C₁ -C₄ straight chain alkyl;

R²¹ is hydrogen or C₁ -C₄ straight chain alkyl;

R²² is pyridinyl or imidazolyl;

alk is a divalent organic radical derived from a straight or branched C₁-C₅ alkane;

a compound of Formula VI ##STR7## wherein: R²³ is C₁ -C₃ alkyl or allyl;

R²⁴ is C₁ -C₃ hydroxyalkyl or C₁ -C₃ dihydroxyalkyl;

R²⁵ is hydrogen or CH₃ ;

a compound of Formula VII ##STR8## a compound of Formula VIII ##STR9##R^(25') is hydrogen or methoxy; a compound of Formula IX ##STR10##wherein: Y^(b), in combination with the carbon atom to which it isjoined, defines a substituted or unsubtituted aromatic heterocyclic5-membered ring selected from the group consisting of ##STR11## R²⁶ ishydrogen, C₁ -C₃ alkyl, allyl, or ##STR12## R²⁷ is hydrogen, C₁ -C₃alkyl, allyl, ##STR13## or (CH₂)_(n') --X"; n' is 1 to 5;

X" is an optionally substituted phenyl, C₁ -C₃ alkoxy, or C₁ -C₃alkylthio;

R²⁸ and R²⁹ are independently hydrogen, C₁ -C₃ alkyl, C₁ -C₃ alkoxy,hydroxy, C₁ -C₃ alkylthio, halo, CN, phenyl; or together are--(CH₂)_(p") --;

p" is 3 to 6;

Y^(a) is --CH₂ --, --O--, --S(O)_(m") --;

m" is 0, 1, or 2; and

a compound of the Formula X ##STR14## or a pharmaceutically acceptablesalt or solvate thereof.

This invention provides a method for treating a mammal suffering from orsusceptible to a condition associated with dysfunctional or abnormal5-HT_(2B) receptor stimulation, comprising administering an effectiveamount of a compound interacting with the 5HT_(2B) receptor as anagonist, partial agonist or antagonist selected from the groupconsisting of a compound of the Formula XI ##STR15## wherein Q' isselected from the group consisting of hydrogen, R₃₄, and (CHR₂)R₄ ;

R₃₄ is selected from the group consisting of spiro-bicyclic, substitutedspiro-bicyclic, bicyclic or substituted bicyclic;

R₁ is hydrogen or C₁ -C₃ alkyl;

R₂ is hydrogen or C₁ -C₆ alkyl;

R₃ is hydrogen or C₁ -C₃ alkyl;

R₄ is C₅ -C₈ cycloalkyl, substituted C₅ -C₈ cycloalkyl, C₅ -C₈cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, bicyclic or substitutedbicyclic;

A is selected from the group consisting of ##STR16## wherein R₆ and R₇are, independently, hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, or OR₅ ;

m is 1 or 2;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₈ is independently selected from the group consisting of an R₆ group,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, C₇ -C₂₀ arylalkyl; or

R₆ and R₇ together with the carbon atoms of group A form a 5- to8-member carbon ring;

R³⁰ and R³¹ join to form a 3 to 8 member carbon ring; or

R³⁰ and R³¹ are independently selected from the group consisting of C₁-C₆ alkyl and C₂ -C₆ alkenyl; or

a pharmaceutically acceptable salt or solvate thereof.

This invention provides a method for treating a mammal suffering from orsusceptible to a condition associated with dysfunctional or abnormal5-HT_(2B) receptor stimulation, comprising administering an effectiveamount of a compound interacting with the 5HT_(2B) receptor as anagonist, partial agonist or antagonist selected from the groupconsisting of a compound of the Formula XII ##STR17## A is selected fromthe group consisting of ##STR18## wherein R₆ and R₇ are, independently,hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo, halo(C₁ -C₆)alkyl, halo(C₂-C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁ -C₆ alkyl)_(m)amino, NO₂, --SR₅, or OR₅ ;

m is 1 or 2;

R₈ is selected from the group consisting of hydrogen, C₁ -C₆ alkyl, C₂-C₆ alkenyl, halo, halo(C₂ -C₆)alkyl, halo(C₁ -C₆)alkenyl, COR₅, C₁ -C₁₀alkanoyl, CO₂ R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, and C₇ -C₂₀ arylalkyl;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₆ and R₇ together with the carbon atoms of group A form a 5- to8-member carbon ring;

R₉ and R₁₀ are independently selected from the group consisting ofhydrogen, C₁ -C₆ alkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁-C₃)alkyl, C₇ -C₂₀ arylalkyl;

R₁₁ is selected from the group consisting of C₁ -C₄ alkyl, OR_(5'),fluoro, bromo, iodo, and chloro;

R³⁰ and R³¹ join to form a 3 to 8 member carbon ring; or

R³⁰ and R³¹ are independently selected from the group consisting of C₁-C₆ alkyl and C₂ -C₆ alkenyl; or

a pharmaceutically acceptable salt or solvate thereof.

Second, this invention provides a method for blocking a 5HT_(2B)receptor in a mammal, comprising administering a 5HT_(2B) receptoroccupying dose of a compound selected from the group consisting ofFormula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or apharmaceutically acceptable salt or solvate thereof.

This invention provides a method for blocking a 5HT_(2B) receptor in amammal, comprising administering a 5HT_(2B) receptor occupying dose of acompound selected from the group consisting of Formula XI, and XIIsupra.; or a pharmaceutically acceptable salt or solvate thereof.

Third, this invention provides a method for selectively interacting withthe 5-HT_(2B) receptor in a mammal, comprising administering a 5-HT_(2B)selective compound selected from the group consisting of Formula I, II,III, IV, V, VI, VII, VIII, IX, and X supra.; or a pharmaceuticallyacceptable salt or solvate thereof to a mammal.

This invention provides a method for selectively interacting with the5-HT_(2B) receptor in a mammal, comprising administering a 5-HT_(2B)selective compound selected from the group consisting of of Formula XIand XII; or a pharmaceutically acceptable salt or solvate thereof to amammal.

The present invention provides compounds of the Formula XI ##STR19##wherein Q' is selected from the group consisting of hydrogen, R₃₄, and(CHR₂)R₄ ;

R₃₄ is selected from the group consisting of spiro-bicyclic, substitutedspiro-bicyclic, bicyclic or substituted bicyclic;

R₁ is hydrogen or C₁ -C₃ alkyl;

R₂ is hydrogen or C₁ -C₆ alkyl;

R₃ is hydrogen or C₁ -C₃ alkyl;

R₄ is C₅ -C₈ cycloalkyl, substituted C₅ -C₈ cycloalkyl, C₅ -C₈cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, bicyclic or substitutedbicyclic;

A is selected from the group consisting of ##STR20## wherein R₆ and R₇are, independently, hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, or OR₅ ;

m is 1 or 2;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₈ is independently selected from the group consisting of an R₆ group,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃) alkyl, C₇ -C₂₀ arylalkyl; or

R₆ and R₇ together with the carbon atoms of group A form a 5- to8-member carbon ring;

R³⁰ and R³¹ join to form a 3 to 8 member carbon ring; or

R³⁰ and R³¹ are independently selected from the group consisting of C₁-C₆ alkyl and C₂ -C₆ alkenyl; or

a pharmaceutically acceptable salt or solvate thereof.

This invention provides compounds of Formula ##STR21## A is selectedfrom the group consisting of ##STR22## wherein R₆ and R₇ are,independently, hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo, halo(C₁-C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁-C₆ alkyl)_(m) amino, NO₂, --SR₅, or OR₅ ;

m is 1 or 2;

R₈ is selected from the group consisting of hydrogen, C₁ -C₆ alkyl, C₂-C₆ alkenyl, halo, halo(C₂ -C₆)alkyl, halo(C₁ -C₆)alkenyl, COR₅, C₁ -C₁₀alkanoyl, CO₂ R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, and C₇ -C₂₀ arylalkyl;

R₅ is independently hydrogen or C₁ -C₄ alkyl;

R_(5') is C₁ -C₄ alkyl;

R₆ and R₇ together with the carbon atoms of group A form a 5- to8-member carbon ring;

R₉ and R₁₀ are independently selected from the group consisting ofhydrogen, C₁ -C₆ alkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁-C₃)alkyl, C₇ -C₂₀ arylalkyl;

R₁₁ is selected from the group consisting of C₁ -C₄ alkyl, OR_(5'),fluoro, bromo, iodo, and chloro;

R³⁰ and R³¹ join to form a 3 to 8 member carbon ring; or

R³⁰ and R³¹ are independently selected from the group consisting of C₁-C₆ alkyl and C₂ -C₆ alkenyl; or

a pharmaceutically acceptable salt or solvate thereof.

Finally this invention provides a method for interacting with a human5-HT_(2B) receptor in a human, comprising administering a 5-HT_(2B)blocking dose of a compound selected from the group consisting ofFormula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.; or apharmaceutically acceptable salt or solvate thereof to a human.

This invention provides a method for interacting with a human 5-HT_(2B)receptor in a human, comprising administering a 5-HT_(2B) blocking doseof a compound selected from the group consisting of Formula XI and XII;or a pharmaceutically acceptable salt or solvate thereof.

A further embodiment of this invention is an article of manufacturecomprising packaging material and one or more pharmaceutical agentscontained within said packaging material, wherein said pharmaceuticalagent is effective for the treatment of a condition requiring 5-HT_(2B)receptor occupation and is selected from the group consisting of acompound of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X supra.;or a pharmaceutically acceptable salt or solvate thereof; and saidpackaging material comprises a label which indicates that saidpharmaceutical agent can be used for the treatment of a conditionrequiring 5-HT_(2B) receptor modulation.

Another embodiment of this invention is an article of manufacturecomprising packaging material and one or more pharmaceutical agentscontained within said packaging material, wherein said pharmaceuticalagent is effective for the treatment of a condition requiring 5-HT_(2B)receptor occupation and is selected from the group consisting of acompound of Formula XI, and XII supra.; or a pharmaceutically acceptablesalt or solvate thereof; and said packaging material comprises a labelwhich indicates that said pharmaceutical agent can be used for thetreatment of a condition requiring 5-HT_(2B) receptor modulation.

DETAILED DESCRIPTION OF THE INVENTION

The term "treating" as used herein includes prophylaxis of the namedphysical and/or mental condition or amelioration or elimination of thedeveloped physical and/or mental condition once it has been established.

The terms "C₁ -C_(n) alkyl" wherein n=2-10, as used herein, represent abranched or linear alkyl group having from one to the specified numberof carbon atoms. Typical C₁ -C₆ alkyl groups include methyl, ethyl,n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl,hexyl and the like.

As used herein, the term "R³⁰ and R³¹ join to form a 3 to 8 membercarbon ring" shall mean that R³⁰ and R³¹ are most preferablyindependently selected from the group consisting of C₁ -C₆ alkyl and C₂-C₆ alkenyl. The carbon ring thus formed may be saturated orunsaturated. As used herein, such ring may be illustrated as: ##STR23##wherein n³⁰ shall refer to the total number of carbon atoms in the ringthus formed. Such carbon ring may be substituted with from one to foursubstituents independently selected from the group consisting ofhydrogen, C₁ -C₆ alkyl, NO₂, halo, halo(C₁ -C₆)alkyl, halo(C₂-C₆)alkenyl, C₂ -C₆ alkenyl, CO₂ R₅, (C₁ -C₆ alkyl)_(m) amino, --SR₅,and OR₅. A preferred embodiment is when R³⁰ and R³¹ join to form a C₃-C₆ member saturated carbon ring. It is another preferred embodimentthat R³⁰ and R³¹ join to form a C₃ -C₅ member saturated carbon ring.

When R³⁰ and R³¹ do not join to form a carbon ring, it is a preferredembodiment that R³⁰ and R³¹ are independently selected from the groupconsisting of C₁ -C₃ alkyl.

The terms "C₂ -C_(n) alkenyl" wherein n=3-10, as used herein, representsan olefinically unsaturated branched or linear group having from 2 to 10carbon atoms and at least one double bond. The groups can be branched orstraight chain. Examples of such groups include 1-propenyl, 2-propenyl(--CH₂ --CH═CH₂), 1,3-butadienyl (--CH═CHCH═CH₂), 1-butenyl (--CH═CHCH₂CH₃), hexenyl, pentenyl, and the like.

The terms "halide", "halogen", and "halo" include fluorine, chlorine,bromine, and iodine. The preferred halogen is chlorine.

The terms "halo(C₁ -C₆)alkyl" and "halo(C₂ -C₆)alkenyl" refer to alkylor alkenyl substituents having one or more independently selected haloatoms attached at one or more available carbon atoms. These termsinclude chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl,trifluoroethylenyl, 3-bromopropyl, 3-bromo-1-propenyl, 2-bromopropyl,2-bromo-1-propenyl, 3-chlorobutyl, 3-chloro-2-butenyl,2,3-dichlorobutyl, chloroethylenyl, 5-fluoro-3-pentenyl,3-chloro-2-bromo-5-hexenyl, 3-chloro-2-bromo-butyl, trichloromethyl,dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl,1,1-dichloropropyl, and the like. More preferred halo-(C₁ -C₆)alkylgroups are trichloromethyl, trichloroethyl, and trifluoromethyl. Themost preferred halo-(C₁ -C₆)alkyl is trifluoromethyl.

The term "C₁ -C₁₀ alkanoyl" represents a group of the formula C(O)(C₁-C₉) alkyl. Typical C₁ -C₁₀ alkanoyl groups include acetyl, propanoyl,butanoyl, and the like.

The term "(C₁ -C₆ alkyl)_(m) amino" wherein m=1-2; refers to either amono- or a dialkylamino group in which the alkyl portion of the groupmay be straight or branched. Examples of such groups are methylamino,dimethylamino, ethylamino, diethylamino, 2-propylamino, 1-propylamino,di(n-propyl)amino, di(iso-propyl)amino, methyl-n-propylamino,t-butylamino, and the like.

The term "C₃ -C_(n) cycloalkyl" wherein n=4-8, represents cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "substituted(C₅ -C_(n)) cycloalkyl" refers to a cycloalkylgroup as described supra wherein the cycloalkyl group may be substitutedwith from one to four substituents independently selected from the groupconsisting of hydrogen, C₁ -C₆ alkyl, NO₂, halo, halo(C₁ -C₆)alkyl,halo(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, CO₂ R₅, (C₁ -C₆ alkyl)_(m) amino,--SR₅, and OR₅.

The term "C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl" represents a linear alkylgroup substituted at a terminal carbon with a C₃ -C₈ cycloalkyl group.Typical cycloalkylalkyl groups include cyclohexylethyl,cyclohexylmethyl, 3-cyclopentylpropyl, and the like.

The term "C₅ -C₈ cycloalkenyl" represents an olefinically unsaturatedring having five to eight carbon atoms, e.g., phenyl, cyclohexadienyl,cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like.

The term "substituted (C₅ -C₈) cycloalkenyl" refers to a cycloalkenylgroup as described supra wherein the cycloalkenyl group may besubstituted with from one to four substituents independently selectedfrom the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halo, halo(C₁-C₆)alkyl, halo(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, COR₅, C₁ -C₁₀ alkanoyl,C₇ -C₂₀ arylalkyl, CO₂ R₅, (C₁ -C₆ alkyl)_(m) amino, --SR₅, and OR₅.

The term "C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl" represents a linear C₁ -C₃alkyl group substituted at a terminal carbon with a C₅ -C₈ cycloalkenylgroup.

The term "aryl" represents phenyl or naphthyl. The aryl group can beunsubstituted or can have one or two substituents independently selectedfrom the group consisting of C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl,substituted C₃ -C₈ cycloalkyl, C₂ -C₆ alkenyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, phenyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl,C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, COR₅, C₁ -C₁₀ alkanoyl, OR₅, and C₇-C₁₆ arylalkyl. The substituents may be located at any availableposition on the aryl ring.

The term "C₇ -C₂₀ arylalkyl" represents an aryl-(C₁ -C₁₀)alkylsubstituent wherein the alkyl group is linear, such as benzyl,phenethyl, 3-phenylpropyl, or phenyl-t-butyl; or branched.

The term "bicyclic" represents either an unsaturated or saturated stable7- to 12-membered bridged or fused bicyclic carbon ring. The bicyclicring may be attached at any carbon atom which affords a stablestructure. The term includes, but is not limited to, naphthyl,dicyclohexyl, dicyclohexenyl, and the like.

The term "unsaturated bicyclic" represents a stable bicyclic ring of 7to 12 carbon atoms. The unsaturated bicyclic ring may be attached at anycarbon atom which affords a stable structure. The unsaturated bicyclicring may be substituted with from one to four substituents as definedfor "substituted bicyclic" infra.

The general term "substituted bicyclic" refers to a bicyclic ring systemwith up to 4 substituents attached at any desired positions on thebicyclic ring system. The bicyclic substituents may be independentlyselected from the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halo,halo(C₁ -C₆)alkyl, halo(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, COR₅, C₁ -C₁₀alkanoyl, C₇ -C₂₀ arylalkyl, CO₂ R₅, (C₁ -C₆ alkyl)_(m) amino, --SR₅,and OR₅ ; wherein R₅ is defined supra. It is intended that thesubstituted bicyclic substituent may bond to the CHR₂ group through anyavailable carbon atom in the bicyclic ring system. The term includes,but is not limited to compounds such as, 2-methyldicyclohexyl,3-hydroxydicyclohexyl, benzocyclohexyl, benzocyclohexenyl,2-methoxybenzocyclohexyl, 6-chlorobenzocyclohexenyl,8-ethenylbenzocyclohexyl, and the like.

The term "spiro-bicyclic" and "substituted spiro-bicyclic" refer to abicyclic or substituted bicyclic (as defined supra.) directly attachedto the carbon of the parent ring at substituent Q'. For illustrationpurposes, a spiro-bicyclic is attached as shown: ##STR24##

The term "naphthyl" refers to a naphthalene ring system substituent, ascommonly used in organic chemistry. The naphthyl substituent may bond tothe CHR₂ group through any available carbon atom in the naphthyl ringsystem. The term "substituted naphthyl" refers to a naphthyl ring systemwith up to 4 substituents attached at any desired positions on thenaphthyl ring system. The naphthyl substituents may be independentlyselected from the "substituted bicyclic" group supra.

The term "phenyl" as used herein refers to an unsubstituted benzene ringsystem. The term "substituted phenyl" refers to a benzene ring systemwith from one to three substituents independently selected from thegroup of bicyclic substituents defined supra; R₅ is defined supra.

The term "C₁ -C₄ alkoxy" represents a straight or branched alkoxy chainhaving from one to four carbon atoms. C₁ -C₄ alkoxy groups includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.

In a compound of Formula IV when m' is 0, the ring attached to the amidenitrogen atom is cyclopentyl; when m is 1, the ring is cyclohexyl; whenm' is 2, the ring is cycloheptyl; and when m' is 3, the ring iscyclooctyl. If the cycloalkyl ring is substituted, the substituent maybe at an available position on the ring.

The term "pyridinyl" refers to 2-, 3-, or 4-pyridinyl. The term"imidazolyl" refers to 1-, 2-, or 4-imidazolyl.

The term "alk" refers to a divalent organic radical derived from astraight or branched C₁ -C₅ alkane. Such groups include but are notlimited to --CH₂ --, --CH(CH₃)--, --C(CH₃)₂ --, --CH(C₂ H₅)--, --CH₂ CH₂--, --CH₂ CH(CH₃)--, --CH₂ C(CH₃)₂ --, --CH₂ CH(CH₃)CH₂ --,--CH(CH₃)CH(CH₃)--, --CH (CH₃)CH₂ CH(CH₃)--, and the like.

The term "optionally substituted phenyl" refers to a phenyl ring whichmay contain one or two substituents selected from the group consistingof C₁ -C₃ alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, NO₂, and CN.

The term "selective interaction with a 5-HT_(2B) receptor" refers to amethod of interacting with the 5-HT_(2B) receptor to a greater extentthan the 5-HT_(2A) or 5-HT_(2C) receptor.

The term "protic acid" refers to an acid having an acidic hydrogen.Preferred protic acids include hydrochloric acid, formic acid,perchloric acid, sulfuric acid, and phosphoric acid in an aqueousmedium. The most preferred protic acids are hydrochloric acid, sulfuricacid, and formic acid.

The term "organic solvent" includes solvents containing carbon, such ashalogenated hydrocarbons, ether, toluene, xylene, benzene, andtetrahydrofuran.

The term "agitate" includes such techniques as stirring, centrifugation,mixing, and other similar methods.

The term "aprotic solvent" refers to polar solvents of moderately highdielectric constant which do not contain an acidic hydrogen. Examples ofcommon aprotic solvents are dimethyl sulfoxide (DMSO),dimethylformamide, sulfolane, tetrahydrofuran, diethylether,methyl-t-butyl ether, or 1,2-dimethoxyethane.

The term "protic solvent" refers to a solvent containing hydrogen thatis attached to oxygen, and hence is appreciably acidic. Common proticsolvents include such solvents as water, methanol, ethanol, 2-propanol,and 1-butanol.

The term "inert atmosphere" refers to reaction conditions in which themixture is covered with a layer of inert gas such as nitrogen or argon.

Abbreviations used herein have their accepted meaning, unless statedotherwise. For example, "Me" and "Et" refer to methyl, ethylrespectively, and "t-Bu" refers to tertiary-butyl. The abbreviation "RT"refers to room temperature or ambient conditions unless indicatedotherwise.

The term "ligand" refers to compounds that are bound by the indicatedreceptor. Compounds useful as selective ligands may be used toselectively occupy the specific receptor site or may act as a selectiveagonist at the specific receptor site.

The term "substantially pure" is intended to mean at least about 90 molepercent, more preferably at least about 95 mole percent, and mostpreferably at least about 98 mole percent of the desired enantiomer orstereoisomer is present compared to other possible configurations.

Compounds which are contemplated for use in modulating a 5-HT_(2B)receptor include, but are not limited to7-bromo-8-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-isopropyl-8-methoxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,5-chloro-8-ethoxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,5-dimethylamino-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-nitro-8-butyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,7-cyclohexyl-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole, 6-3-methyl-cyclohexyl!-8-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-benzyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,5-cyclohexylmethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-carboxyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-ethoxy-8-isopropyl-3-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6,8-dichloro-4-naphthylmethyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,7,8-difluoro-2(N)-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6,8-dibutyl-2(N)-cyclopropylmethyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole,6,8-dibromo-2(N)-cyclohexenylmethyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 8-chloro-2(N)-benzyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole,8-fluoro-4-methyl-2(N)-cyclohexyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 6-methylamine-8-chloro-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 6-chloromethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 7-methoxy-1-naphthylpiperazine, 1-naphthylpiperazine,7-bromo-1H-indole-3-ethanamine, 7-fluoro-1H-indole-3-ethanamine,7-methoxy-1H-indole-3-ethanamine, 7-chloro-1H-indole-3-ethanamine,5-methyl-7-chloro-1H-indole-3-ethanamine,1-H-Benz(G)indole-3-ethanamine,6-methyl-7-chloro-1H-indole-3-ethanamine,6-bromo-7-methyl-1H-indole-3-ethanamine,6-methyl-1H-indole-3-ethanamine,5-methyl-7-bromo-1H-indole-3-ethanamine,6,7-dimethyl-1H-indole-3-ethanamine,6-methyl-7-bromo-1H-indole-3-ethanamine,(8β)-N-cyclohexyl-1-isopropyl-6-n-butyl-ergoline-8-carboxamide,(8β)-N-cyclohexyl-N-ethyl-1-isopropyl-6-methylergoline-8-carboxamide,other (8β)-1-alkyl-6-(substituted)ergolines described in U.S. Pat. No.4,931,447, cycloalkylamides of (8β)-alkyl-6-(substituted)ergolinesdescribed in U.S. Pat. No. 4,981,859, compounds described in U.S. Pat.No. 4,563,461, compounds described in U.S. Pat. No. 4,902,691, whereinthe four aforementioned U.S. Patents are herein incorporated byreference, 1,2-dimethyl-3-ethyl-5-(dimethylamino)-indole,2-(di-n-propylamino)-8-(isothiazol-3-yl)-1,2,3,4-tetrahydronaphthalene,2-ethylamino-8-(isoxazol-3-yl)-1,2,3,4-tetrahydronaphthalene,2-(N-methyl-N-benzylamino)-8-(5-n-propyl-1,2,3-oxadiazol-4-yl)-1,2,3,4-tetrahydronaphthalene,2-diallylamino-8-(pyrazol-3-yl)-1,2,3,4-tetrahydronaphthalene,2-diethylamino-8-(1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(3-methoxypyrid-2-yl)-1,2,3,4-tetrahydronaphthalene,2-benzylmethylamino-8-(3-methoxypyrid-2-yl)-1,2,3,4-tetrahydronaphthalene,2-benzylmethylamino-8-(benzofuran-2-yl)-1,2,3,4-tetrahydronaphthalene,2-dimethylamino-8-(1,3,5-triazin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-cyclopropylmethylamino)-8-(oxazol-4-yl)-1,2,3,4-tetrahydronaphthalene,2-ethylamino-8-(1,2,3-oxadiazol-4-yl)-thio-1,2,3,4-tetrahydronaphthalene,2-n-butylamino-8-(5-methoxypyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(5-chlorooxazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(pyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(3-methyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(pyrazin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-6-(bromopyrazin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(benzothiazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(benzoxazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(indol-3-yl)-1,2,3,4-tetrahydronaphthalene,3-(di-n-propylamino)-5-(isoxazol-2-yl)-1,2,3,4-tetrahydronaphthalene,3-(di-n-propylamino)-5-(isoxazol-2-yl)-chromane,5-(isoxazol-5-yl)-3-(dipropylamino)chromane,5-(3-methylisoxazol-5-yl)-3-(dipropylamino)chromane,5-(4-methylisoxazol-5-yl)-3-(dipropylamino)chromane,5-(3,4-dimethylisoxazol-5-yl)-3-(dipropylamino)chromane,5-(3-methylisoxazol-5-yl)-3-(dipropylamino)thiochromane,5-(4-methylisoxazol-5-yl)-3-(dipropylamino)thiochromane,5-(3,4-dimethylisoxazol-5-yl)-3-(dipropylamino)thiochromane,8-(4,5,6,7-tetrahydrobenzc!isoxazol-1-yl)-2-(dimethylamino)tetrahydronaphthalene, and the like.

Especially preferred compounds for use in modulating a 5-HT_(2B)receptor include 7-bromo-8-methyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 6-isopropyl-8-methoxy-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 5-chloro-8-ethoxy-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 6-chloro-7-methyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 5-dimethylamino-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 6-nitro-8-butyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,7-cyclohexyl-8-hydroxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole, 6-3-methyl-cyclohexyl!-8-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-benzyl-8-fluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,5-cyclohexylmethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-carboxyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6-ethoxy-8-isopropyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6,8-dichloro-4-naphthylmethyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6,8-dimethyl-3,4-dimethyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,7,8-difluoro-2(N)-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole,6,8-dibutyl-2(N)-cyclopropylmethyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole,6,8-dibromo-2(N)-cyclohexenylmethyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 8-chloro-2(N)-benzyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole,8-fluoro-4-methyl-2(N)-cyclohexyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole,6-methylamine-8-chloro-3-isopropyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 6-chloromethyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole, 7-methoxy-1-naphthylpiperazine, 1-naphthylpiperazine,7-bromo-1H-indole-3-ethanamine, 7-fluoro-1H-indole-3-ethanamine,7-methoxy-1H-indole-3-ethanamine, 7-chloro-1H-indole-3-ethanamine,5-methyl-7-chloro-1H-indole-3-ethanamine,1-H-Benz(G)indole-3-ethanamine,6-methyl-7-chloro-1H-indole-3-ethanamine,6-bromo-7-methyl-1H-indole-3-ethanamine,6-methyl-1H-indole-3-ethanamine,5-methyl-7-bromo-1H-indole-3-ethanamine,6,7-dimethyl-1H-indole-3-ethanamine,6-methyl-7-bromo-1H-indole-3-ethanamine,1,2-dimethyl-3-ethyl-5-(dimethylamino)-indole,2-(di-n-propylamino)-8-(isothiazol-3-yl)-1,2,3,4-tetrahydronaphthalene,2-ethylamino-8-(isoxazol-3-yl)-1,2,3,4-tetrahydronaphthalene,2-(N-methyl-N-benzylamino)-8-(5-n-propyl-1,2,3-oxadiazol-4-yl)-1,2,3,4-tetrahydronaphthalene,2-diallylamino-8-(pyrazol-3-yl)-1,2,3,4-tetrahydronaphthalene,2-diethylamino-8-(1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(3-methoxypyrid-2-yl)-1,2,3,4-tetrahydronaphthalene,2-benzylmethylamino-8-(3-methoxypyrid-2-yl)-1,2,3,4-tetrahydronaphthalene,2-benzylmethylamino-8-(benzofuran-2-yl)-1,2,3,4-tetrahydronaphthalene,2-dimethylamino-8-(1,3,5-triazin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-cyclopropylmethylamino)-8-(oxazol-4-yl)-1,2,3,4-tetrahydronaphthalene,2-ethylamino-8-(1,2,3-oxadiazol-4-yl)-thio-1,2,3,4-tetrahydronaphthalene,2-n-butylamino-8-(5-methoxypyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(5-chlorooxazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(pyrimidin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(2-aminopyrimidin-4-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(3-phenyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(3-methyl-1,2,4-oxadiazol-5-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(pyrazin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-6-(bromopyrazin-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(benzothiazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(benzoxazol-2-yl)-1,2,3,4-tetrahydronaphthalene,2-(di-n-propylamino)-8-(indol-3-yl)-1,2,3,4-tetrahydronaphthalene,5-(isoxazol-5-yl)-3-(dipropylamino)chromane,5-(3-methylisoxazol-5-yl)-3-(dipropylamino)chromane,5-(4-methylisoxazol-5-yl)-3-(dipropylamino)chromane,5-(3,4-dimethylisoxazol-5-yl)-3-(dipropylamino)chromane,5-(3-methylisoxazol-5-yl)-3-(dipropylamino)thiochromane,5-(4-methylisoxazol-5-yl)-3-(dipropylamino)thiochromane,5-(3,4-dimethylisoxazol-5-yl)-3-(dipropylamino)thiochromane,8-(4,5,6,7-tetrahydrobenzc!isoxazol-1-yl)-2-(dimethylamino)tetrahydronaphthalene, and3-(di-n-propylamino)-5-(isoxazol-2-yl)-1,2,3,4-tetrahydronaphthalene.

A preferred compound of Formula IX has the following structure:##STR25## Wherein R²⁶, R²⁷, R²⁸, R²⁹, and Y^(a) are as defined supra.

When Q is hydrogen, preferred compounds of Formula I have the followingstructure: ##STR26## Wherein R⁶ is selected from the group consisting ofC₁ -C₄ alkyl, OR_(5'), fluoro, bromo, and chloro;

R_(5') is C₁ -C₄ alkyl; and

R₁, R₇, and R₈ are as defined supra.

The 5-HT_(2B) receptor has been identified in various tissues and organsin the rat. The primary areas of 5-HT_(2B) receptor localization in therat include lung, uterus, bladder, stomach, and colon. Further, the5-HT_(2B) receptor has been identified in various tissues and organs inthe human. Interesting areas of 5-HT_(2B) receptor localization in thehuman include but are not limited to the brain and blood vessels.

In light of the receptor localization, physiological conditions whichcan be mediated by the 5-HT_(2B) receptor include incontinence, bladderdysfunction, Functional Bowel Disorders, stomach emptying disorders,respirator/disorders including astra, uterine dysfunction includingendometriosis, fibrosis, and motility disorders such as but not limitedto induction of labor, sleeping disorders, eating disorders, includingbulimia and obesity, consumption disorders, thermoregulation, sexualdisorders, hyperactivity, excessive aggression, alcoholism, anxiety,obsessive-compulsive disorders, depression, psychosis, schizophrenia andschizophreniform disorders, panic disorders, Gilles de la Tourettesyndrome, and Alzheimer's disease and cardiovascular diseases such asthrombosis, hypertension, vasospasm (peripheral and/or central) such asstroke, angina, and other vascular occlusive diseases. Further, migraineheadaches can be treated using 5-HT_(2B) receptor stimulating compoundsof this invention. Preferred examples of such conditions which may betreated using 5-HT_(2B) modulators include cardiovascular disorders,uterine dysfunction, sleep disorders, hallucinogenic activity,psychosis, anxiety, depression, thermoregulation, feeding disorders, andhypotension. See Leonard, B. E., International ClinicalPsychopharmacology, 7, 13-21 (1992). It is particularly preferred to usea 5-HT_(2B) antagonist for treating a Functional Bowel Disorder.

Several examples of more specific CNS disorders which may be treatedusing 5-HT_(2B) modulating compounds of this invention include, but arenot limited to: (numerals in parenthesis refer to the DSM-III-RClassification Codes) Attention-deficit hyperactivity disorder (314.01),conduct disorders (312.20, 312.00, 312.90), primary degenerativedementia of the Alzheimer type, senile onset (290.30, 290.20, 290.21,290.00), primary degenerative dementia of the Alzheimer type, presenileonset (290.11, 290.12, 290.13, 290.10), alcohol withdrawal delirium(291.00), alcohol hallucinosis (291.30), alcohol, dementia associatedwith alcoholism (291.20), cannabis, delusional disorder (292.11),cocaine, intoxication (305.60), hallucinogen, mood disorder (292.84),nicotine withdrawal (292.00), phencyclidine or similarly actingarylcyclohexylamine intoxication (305.90), other psychoactive substanceintoxication (305.90), delirium (293.00), dementia (294.10), organicdelusional disorder (293.81), organic hallucinosis (293.82), organicmood disorder (293.83), organic anxiety disorder (294.80), organicpersonality disorder (310.10), organic mental disorder (294.80),schizophrenia, catatonic (295.21, 295.22, 295.23, 295.24, 295.25,295.20), schizophrenia, disorganized (295.11, 295.12, 295.13, 295.14,295.15, 295.00), schizophrenia, paranoid (295.31, 295.32, 295.33,295.34, 295.35, 295.00), schizophrenia, undiffertiated (295.91, 295.92,295.93, 295.94, 295.95, 295.00), schizophrenia, residual (295.61,295.62, 295.63, 295.64, 295.65, 295.60), delusional (paranoid disorder(297.10), schizophreniform disorder (295.40), schizoaffective disorder(295.70), induced psychotic disorder (297.30), bipolar disorder, mixed(296.61, 296.62, 296.63, 296.64, 296.65, 296.66, 296.60), bipolardisorder, manic (296.41, 296.42, 296.43, 296.44, 296.45, 296.46,296.40), bipolar disorder, depressed (296.51, 296.52, 296.53, 296.54,296.55, 296.56, 296.50), major depression, single episode (296.21,296.22, 296.23, 296.24, 296.25, 296.26, 296.20), major depression,recurrent (296.31, 296.32, 296.33, 296.34, 296.35, 296.36, 296.30),obsessive compulsive disorder (300.30), post-traumatic stress disorder(309.89), generalized anxiety disorder (300.02), hypochondriasis(300.07), somatization disorder (300.81), male erectile disorder(302.72), intermittent explosive disorder (312.34), impulse controldisorder (312.39), paranoid (301.00), schizoid (301.20), schizotypal(301.22), antisocial (301.70), and borderline (301.83). Diagnostic andStatistical Manual of Mental Disorders, 3rd Ed. Revised, (1980),prepared by the Task Force on Nomenclature and Statistics of theAmerican Psychiatric Association.

Thus, the present invention also provides methods for treating orpreventing the above-named conditions.

The skilled artisan will recognize that psychosis or psychoticconditions are characterized by hallucinations, delusions, or grosslydisorganized behavior which indicate that the patient suffers from grossimpairment in reality testing. Therefore, drugs having antipsychoticactivity can be useful for treating a variety of important psychoticconditions.

As used herein the term "Functional Bowel Disorder" refers to afunctional gastrointestinal disorder manifested by (1) abdominal painand/or (2) symptoms of disturbed defecation (urgency, straining, feelingof incomplete evacuation, altered stool form consistency! and alteredbowel frequency/timing) and/or (3) bloating (distention). The term"Functional Bowel Disorder" includes but is not limited to irritablebowel syndrome, hypermotility, ichlasia, hypertonic lower esophogealsphinctor, tachygastria, constipation, hypermotility associated withirritable bowel syndrome.

Functional Bowel Disorders are characterized by abnormal bowel functionwithout detectable structural abnormalities. Abnormal bowel functionincludes diarrhea, constipation, mucorrhea, and pain or discomfort overthe course of the sigmoid colon. Such disorders are influenced bypsychological factors and stressful life situations.

The Functional Bowel Disorder, Irritable Bowel Syndrome (IBS), is one ofthe most commonly encountered gastrointestinal disorders. Between 20%and 50% of patients referred to gastrointestinal clinics suffer fromIBS. Symptoms of IBS occur in approximately 14% of otherwise apparentlyhealthy people. IBS is a complex condition, in part because it is not adisease but a syndrome composed of a number of conditions with similarmanifestations.

Current therapy for Functional Bowel Disorders is restricted to drugswhich treat only a small proportion of patients. For example,anticholinergic drugs reduce spasticity, thereby relieving some of theabdominal pain. Histamine H2 receptor antagonists inhibit gastric acidsecretion and my relieve some dyspeptic symptoms. A therapeutic agentthat relieves most of the Functional Bowel Disorder symptoms iscurrently not available.

The term Functional Bowel Disorder includes conditions such as IrritableBowel Syndrome, ichlasia, hypertonic lower esophogeal sphincter,tachygastria, hypermotility associated with irritable bowel syndrome,and constipation.

The compounds described herein can form acid addition salts with a widevariety of inorganic and organic acids. Typical acids which can be usedinclude sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric,hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric,cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic,benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and thelike. The pharmaceutically acceptable acid addition salts are especiallypreferred for the treatment of 5-HT_(2B) receptor related conditions.

Certain compounds are preferred for use in treating conditions relatedto the modulation of a 5-HT_(2B) receptor. The following inventionembodiments and compound characteristics listed in tabular form may beindependently combined to produce a variety of preferred compounds andembodiments of the invention. The following list of embodiments of thisinvention is in no way intended to limit the scope of this invention inany way:

A) R₁ is hydrogen;

B) R₂ is hydrogen or methyl;

C) R₃ is hydrogen or methyl;

D) R₄ is C₅ -C₈ cycloalkenyl or substituted C₅ -C₈ cycloalkenyl,bicyclic or substituted bicyclic, wherein the substituents are selectedfrom the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halo, halo(C₁-C₆)alkyl, C₂ -C₆ alkenyl, COR₅, (C₁ -C₆ alkyl)_(m) amino, --SR₅, andOR₅.

E) A is a group of formula III;

F) A is a group of formula IV wherein R₆ and R₇ are C₁ -C₆ alkyl orhalo, and R₈ is hydrogen, C₁ -C₅ alkyl, halo, C₅ -C₈ cycloalkyl, phenylor substituted-phenyl;

G) The compound interacting with the 5-HT_(2B) receptor is a 5-HT_(2B)receptor antagonist;

H) The compound interacting with the 5-HT_(2B) receptor is a 5-HT_(2B)receptor partial agonist;

I) R₄ is substituted C₅ -C₈ cycloalkenyl; wherein the substituents areselected from the group consisting of hydrogen, NO₂, halo, (C₁ -C₆alkyl)_(m) amino, and OR₅ ;

J) A is a group of formula IV wherein R₆ is hydrogen, R₇ and R₈ areindependently selected from the group consisting of halo and C₁ -C₄alkyl;

K) R₄ is naphthyl or substituted naphthyl wherein the naphthylsubstituents are selected from the group consisting of (C₁ -C₆alkyl)_(m) amino and OR₅ ;

L) Y^(a) is CH₂, R²⁶ and R²⁷ are each C₂ -C₃ alkyl; and R²⁸ and R²⁹ areeach hydrogen;

M) Compounds of the Formula I, II, III, IV, and V;

N) Compounds of the Formula II, III, and VIII;

O) Compounds of the Formula VI, VIII, IX, XI, and XII;

P) A compound of the Formula X;

Q) Compounds of wherein R₆ is methyl, R₂ is methyl, and R₄ issubstituted alkenyl wherein the alkenyl group is phenyl and there aretwo substituents which are each methoxy;

R) The 5-HT_(2B) modulated condtion is a Functional Bowel Disorder.

S) The Functional Bowel Disorder is irritable bowel syndrome.

T) The 5-HT_(2B) modulated condition is psychosis.

U) The 5-HT_(2B) selective compound has a greater affinity for 5-HT_(2B)receptors than it has for 5-HT2A receptors.

V) The 5-HT_(2B) selective compound has a greater affinity for 5-HT_(2B)receptors than it has for 5-HT_(2C) receptors.

W) The 5-HT_(2B) modulated condtion is selected from the groupconsisting of urinary incontinence, bladder dysfunction, uterinedysfunction, cardiovascular disorder, and respiratory disorder.

X) The compound is administered in a unit dosage form.

Y) The label on the article of manufacture states that the compound isuseful for treating a condition selected from the group consisting ofurinary incontinence, bladder dysfunction, uterine dysfunction,cardiovascular disorder, respiratory disorder, and Functional BowelDisorder.

Z) A pharmaceutical formulation comprising one or more pharmaceuticallyacceptable exipients and a 5-HT_(2B) receptor modulating compound;

Z1) A compound wherein R₄ is aromatic;

Z2) A compound wherein R₄ is an aromatic bicyclic;

Z3) A compound of Formula VII.

Certain compounds of Formula II are useful for modulating 5HT_(2B)receptors. Certain compounds of Formula II within the scope of thisinvention are preferred for that use. The following inventionembodiments and compound characteristics listed in tabular form may beindependently combined to produce a variety of preferred compounds andembodiments of the invention. The following list of embodiments of thisinvention is in no way intended to limit the scope of this invention inany way.

A) R₉ and R₁₀ are each hydrogen.

B) R₁₁ is C₁ -C₃ alkyl.

C) R₁₁ is chloro, fluoro, or bromo.

D) R₁₁ is --OCH₃.

E) R₆ is C₁ -C₄ alkyl.

F) R₆ is methyl.

G) A method for binding a 5HT_(2B) receptor using one or more compoundsof Formula I and/or II.

H) A method of using one or more compounds of Formula I and/or II fortreating a functional bowel disorder.

I) A method of using one or more compounds of Formula I and/or II whichare useful for stimulation of the 5HT_(2B) receptor for treating acondition selected from the group consisting of urinary incontinence,bladder dysfunction, uterine dysfunction, cardiovascular disorders, andrespiratory disorders.

J) A method for using one or more compounds of Formula I and/or II fortreating Irritable Bowel Syndrome.

K) A pharmaceutical formulation comprising a compound of Formula I or IIand one or more pharmaceutically acceptable excipients.

The compounds of the present invention are useful for modulating orblocking the 5-HT₂ receptor. Certain of the present compounds of FormulaXI and XII are preferred for that use. The following inventionembodiments and compound characteristics listed in tabular form may beindependently selected or combined to produce a variety of preferredcompounds and embodiments of the invention. The following list ofembodiments of this invention is in no way intended to limit the scopeof this invention in any way.

A) R₁ is hydrogen;

B) R₂ is hydrogen or methyl;

C) R₃ is hydrogen or methyl;

D) R₄ is C₅ -C₈ cycloalkenyl or substituted C₅ -C₈ cycloalkenyl, whereinthe substituents are selected from the group consisting of hydrogen, C₁-C₆ alkyl, NO₂, halo, halo(C₁ -C₆)alkyl, C₂ -C₆ alkenyl, COR₅, (C₁ -C₆alkyl)_(m) amino, --SR₅, and OR₅ ;

E) A is a group of formula III;

F) A is a group of formula IV wherein R₆ and R₇ are C₁ -C₆ alkyl orhalo, and R₈ is hydrogen, C₁ -C₅ alkyl, halo, C₅ -C₈ cycloalkyl, phenylor substituted-phenyl;

G) R₂ is hydrogen;

H) R₃ is hydrogen;

I) R₄ is substituted C₅ -C₈ cycloalkenyl; wherein the substituents areselected from the group consisting of hydrogen, NO₂, halo, (C₁ -C₆alkyl)_(m) amino, and OR₅ ;

J) A is a group of formula IV wherein R₆ is hydrogen, R₇ and R₈ areindependently selected from the group consisting of halo and C₁ -C₄alkyl.

K) Q' is (CHR₂)R₄ ;

L) R³⁰ and R³¹ join to form a 3 to 6 member carbon ring;

M) R³⁰ and R³¹ join to form a 3 to 5 member carbon ring;

N) R³⁰ and R³¹ are each methyl;

O) R₄ is naphthyl;

P) R₄ is an optionally substituted bicyclic hydrocarbon ring systemhaving 7 to 12 carbon atoms and 0, 1, 2, or 5 double bonds;

Q) R₄ is a 6 to 10 carbon atom unsaturated bicyclic ring system;

R) Q' is bicyclic or substituted bicyclic;

S) R₃₄ is ##STR27## T) R₃₄ is an optionally substituted bicyclic ringsubstituent; U) R₉ and R₁₀ are each hydrogen;

V) R₉ is selected from the group consisting of C₁ -C₆ alkyl, substitutedC₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl,C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, C₇ -C₂₀ arylalkyl;

W) R₄ is aromatic;

X) R₃₄ is spiro-bicyclic or substituted spiro-bicyclic;

Y) Q' is hydrogen.

The more preferred classes have the following features:

A-C, E or F, I, L, N, P, R, and W.

The most preferred class of compounds has the following features:

A, G-J, M, and Q.

The preferred classes of compounds for use as selective 5-HT_(2B)ligands have the following features:

A-D, E or J, M, and O.

The most preferred class of compounds for use as selective 5-HT_(2B)ligands has the following features:

A, G-J, M, and O.

Compounds of Formulas XI and XII are particularly useful for modulating5HT_(2B) receptors. Certain compounds within the scope of this inventionare preferred for that use. The following invention embodiments andcompound characteristics listed in tabular form may be independentlyselected or combined to produce a variety of preferred compounds andembodiments of the invention. The following list of embodiments of thisinvention is in no way intended to limit the scope of this invention inany way.

A) R₉ and R₁₀ are each hydrogen;

B) R₁₁ is C₁ -C₃ alkyl;

C) R₁₁ is chloro, fluoro, or bromo;

D) R₁₁ is --OCH₃ ;

E) R³⁰ and R³¹ join to form a 3 to 8 member carbon ring;

F) R³⁰ and R³¹ join to form a 3 to 6 member carbon ring;

G) A compound having preferred characteristics described supra.;

H) A method for binding a 5HT_(2B) receptor using one or more compoundsof Formula XI and/or XII;

I) A method of using one or more compounds of Formula XI and/or XII fortreating a functional bowel disorder.

I) A method of using one or more compounds of Formula XI and/or XIIwhich are useful for modulatation of the 5HT_(2B) receptor for treatinga function bowel disorder.

J) A method for using one or more compounds of Formula XI and/or XII fortreating Irritable Bowel Syndrome.

K) A pharmaceutical formulation comprising a compound of Formula XIand/or XII and one or more pharmaceutically acceptable excipients.

Examples of compounds of Formula XI include but are not limited to:10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo 2,3-c!quinotine,8-chloro-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo 2,3-c!quinoline,6-(2,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,7-fluoro-6-(2,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,8-methoxy-6-(2,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,7-nitro-6-(3,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,5-(2,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,7-bromo-5-(2,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,6-ethoxy-5-(3,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,7-nitro-6-(3,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,10c-octahydro-1H-indolo2,3-c!quinoline,7-(3,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,7-nitro-6-(3,4-diethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, 6-methyl-8-bromo-1-(3,4-dimethoxyphenyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline,7-(1,1-dimethylethyl)-5-(1-naphthalenyl-1-ethyl)-1,2,3,4,4a,5,6,10c-pyrido3,4-b!indole hydrochloride,7-methyloxy-1-(2-methylaminonaphthalenyl)-1-ethyl)-1,2,3,4,4a,5,6,10c-octahydrocyclopentaa!pyrido 3,4-b!indole, (Z)2-butenedioate,6-(1,1-dimethylethyl)-1-(1-(3-diethylaminonaphthalenyl)-1-ethyl)-1,2,3,4,4a,5,6,10c-octahydrocyclopentaa!pyrido- 3,4-b!indole hydrochloride, and 6-methyl-5-(4-dimethylamino-naphthalenyl)-methyl!-1,2,3,4,4a,5,6,10c-octahydrocyclopentaa!pyrido- 3,4-b!indole dihydrochloride.

Examples of compounds of Formula XII include but are not limited to:3-(2-amine-cyclopentyl)-6,7-dimethylindole,3-(2-amine-cyclopentyl)-5-methyl-7-bromoindole,3-(2-amine-cyclopentyl)-6-methyl-7-chloroindole,3-(2-amine-cyclopentyl)-6-bromo-7-methylindole,3-(2-amine-cyclopentyl)-Benz(G)indole,3-(2-amine-cyclohexyl)-5-methyl-7-chloroindole,3-(2-amine-cyclohexyl)-7-chloroindole,3-(2-amine-cyclopropyl)-7-methoxyindole,3-(2-amine-cycloheptyl)-7-fluoroindole,3-(2-amine-cyclohexyl)-7-bromoindole,3-(2-amine-cyclopropyl)-6-methyl-7-bromoindole,3-(2-amine-cyclopentyl)-5-fluoro-7-methoxyindole,3-(2-amine-cyclopentyl)-5-nitro-7-chloroindole,3-(2-amine-cyclooctyl)-2-ethyl-7-fluoroindole, and3-(2-amine-cycloheptyl)-2-methyl-7-fluoroindole.

The compounds which are useful for blocking 5-HT_(2B) receptorscontemplates racemic mixtures as well as the substantially purestereoisomers of the compounds of Formulas I through XII. The term"enantiomer" is used herein as commonly used in organic chemistry todenote a compound which rotates the plane of polarization. Thus, the "-enantiomer" rotates the plane of polarized light to the left, andcontemplates the levorotary compound of Formulas I through XII. The +and - enantiomers can be isolated using well-known classical resolutiontechniques. One particularly useful reference which describes suchmethods is JACQUES et. al. ENANTIOMERS, RACEMATES, AND RESOLUTIONS (JohnWiley and Sons 1981). Appropriate resolution methods include directcrystallization, entrainment, and crystallization by optically activesolvents. Chrisey, L. A. Heterocycles, 267, 30 (1990). A preferredresolution method is crystallization with an optically active acid or bychiral synthesis as described in Example 46 using the method of A. I.Meyers. Loewe, M. F. et al., Tetrahedron Letters, 3291, 26 (1985),Meyers, A. I. et al., J. Am. Chem. Soc., 4778, 110 (1988). Preferredoptically active acids include camphorsulfonic and derivatives oftartaric acid.

The present invention encompasses both the R and the S configurations.The terms "R" and "S" are used herein as commonly used in organicchemistry to denote the specific configuration of a chiral center. See,R. T. Morrison and R. N. Boyd, Organic Chemistry, pp 138-139 (4th Ed.Allyn & Bacon, Inc., Boston) and Orchin, et al. The Vocabulary ofOrganic Chemistry, p. 126, (John Wiley and Sons, Inc.).

For example, the present invention includes, but is not limited to, theuse of compounds such as (-)-(S)-7-methyl-8-bromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole;(-)-(S)-5,7-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4-b!indole;(-)-(S)-5-fluoro-6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole; and (-)-(S)-6-methyl-1,2,3,4-tetrahydro-1-(3,4-dimethylphenyl)methyl!-9H-pyrido 3,4-b!indole. The invention alsoincludes, but is not limited to, the use of (+)-(S)-7-methyl-8-bromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole;(+)-(S)-5,7-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4-b!indole;(+)-(S)-5-fluoro-6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole; (-)-(R)-7-methyl-8-bromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole;(-)-(R)-5,7-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4-b!indole;(-)-(R)-5-fluoro-6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole; and (-)-(R)-6-methyl-1,2,3,4-tetrahydro-1-(3,4-dimethylphenyl)methyl!-9H-pyrido 3,4-b!indole;(+)-(R)-7-methyl-8-bromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole;(+)-(R)-5,7-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4-b!indole;(+)-(R)-5-fluoro-6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole; and (+)-(S)-6-methyl-1,2,3,4-tetrahydro-1-(3,4-dimethylphenyl)methyl!-9H-pyrido 3,4-b!indole.

The compounds which are useful for interaction with 5-HT_(2B) receptorsare known to form hydrates and solvates with appropriate solvents.Preferred solvents for the preparation of solvate forms include water,alcohols, tetrahydrofuran, DMF, and DMSO. Preferred alcohols aremethanol and ethanol. Other appropriate solvents may be selected basedon the size of the solvent molecule. Small solvent molecules arepreferred to facilitate the corresponding solvate formation. The solvateor hydrate is typically formed in the course of recrystallization or inthe course of salt formation. One useful reference concerning solvatesis Sykes, Peter, A Guidebook to Mechanism in Organic Chemistry, 6, 56,(1986, John Wiley & Sons, New York). The term "solvate" as used hereinincludes hydrate forms such as monohydrate and dihydrates.

Some of the compounds which are useful for interaction with 5-HT_(2B)receptors are either known in the art or readily available by routinesynthetic processes. For example, compounds of Formula III can beprepared using the methods taught in Semonsky et al., U.K. Patent No.816,273 (Jul. 8, 1959), U.S. Pat. Nos. 2,736,728 and 2,774,763 whichU.S. Patents are hereby incorporated by reference. Compounds of FormulaIV may be prepared as described in U.S. Pat. Nos. 4,981,859 and4,931,447 which are hereby incorporated by reference. A process forpreparing compounds of Formula V is described in U.S. Pat. No. 4,902,691which is hereby incorporated by reference. A process for preparingcompounds of Formula VI is described in U.S. Pat. No. 4,563,461 which ishereby incorporated by reference. A compound of Formula VII can beprepared as described in Forbes, I. T., J. Med. Chem., 36:1104-1107(1993). A compound of Formula VIII is known in the art and may bepurchased or prepared by recognized methods. A process for preparingcompounds of Formula IX is available to the artisan in the publishedEuropean Patent application. The European Publication number is 0498590A1 (Aug. 12, 1992; Bulliten 92/33) and is readily available to theUnited States artisan in the English language. A compound of Formula Xis known in the art and can be prepared by recognized methods.

The compounds of the present invention can be prepared using chemicalprocesses that are understood in the art; however, the most preferredmethod for preparing the formula I compounds of this invention utilizesthe process of Scheme V. The most preferred method for preparing acompound of Formula II is using the general method illustrated in SchemeII infra. Compounds of Formula II wherein R₉, R₁₂, and/or R₁₀ are nothydrogen can be prepared using accepted chemical methods such asreductive alkylation and direct alkylation of the correspondingtryptamine.

A compound of Formula I, wherein Q is hydrogen, may be prepared bycontacting glyoxylic compound of formula (i) with an amine of formula(h). This Pictet-Spengler type reaction is generally applicable,provides desirable yields, and produces stable intermediates. Further,the product of the reaction typically may be directly isolated as thedesired salt.

The compounds of formula (a) which may be used as starting materials forthe compounds of the instant invention can be purchased fromart-recognized vendors or may be prepared using well-known chemicaltechniques. The compounds of formula (b) which are useful as startingmaterials for the compounds of this invention may be prepared asrepresented by Scheme I. The R₄ group is as defined herein above.

The process for preparing the compounds of this invention will bediscussed in greater detail in the following paragraphs. ##STR28##

Compound (a) in Scheme I may be substituted or unsubstituted dependingon the desired product. Most formula (a) compounds necessary for thepreparation of the azalactone (b) starting materials are commerciallyavailable. Additional substituted formula (a) compounds may preparedusing common chemical methods. Furniss, B. S. et al., Vogel's Textbookof Practical Organic Chemistry (John Wiley, New York, N.Y. 1989) seeespecially pp 989 through 993.

Generally, the Scheme I reaction is begun by preparing a solution ofcompound (a), acetylglycine and sodium acetate in acetic anhydride. Thereaction is commonly heated from about 90° C. to about 110° C. for aperiod of about 2-15 hours. The reaction mixture is cooled to aboutambient temperature and stirred for a period of about 0-10 hours underinert conditions. The reaction time will vary depending on the degree ofsubstitution on the R₄ group and the completion of reaction desired.

When the reaction is complete, the mixture is poured onto ice withstirring. The azalactone (b) may be isolated by standard isolationtechniques such as filtration and may be dried under reduced pressure.

Compound (d) in Scheme II is used as a starting material for compoundsof Formula I. These compounds are commercially available or may beprepared using the well-known Fischer indole synthesis applied totryptamines. The Fischer synthesis is represented by Scheme II. "A" isas hereinabove defined. ##STR29##

The chlorobutanal compound used in Scheme II may be prepared through thehydrogenation of chlorobutyryl chloride. The hydrogenation may befacilitated by the use of a catalyst such as Pd/C. Other halobutanalcompounds may be suitable for the Scheme II process. The startingcompounds (c) in Scheme II may be purchased or prepared using knownmethods. March, J., Advanced Organic Chemistry Reactions, Mechanisms,and Structure, 3rd (John Wiley & Sons, New York, 1985) see especiallypage 1163.

The Fischer synthesis is commonly begun by adding a suitable saturatedbase like sodium carbonate to a stirred suspension of the hydrazine saltin an organic solvent like chloroform. The hydrazine hydrochloride saltis one especially preferred hydrazine salt. The desired hydrazine freebase is extracted with the organic phase. The oil is placed in analcohol and water solution and treated with an appropriate base likesodium acetate. The halobutanal is added and the tube purged with aninert gas like nitrogen. The resulting mixture is placed in an oil bathwhich has been heated to about 90° C.-110° C. The mixture should beheated for about 17 to 19 hours. The mixture is allowed to cool toambient temperature and is concentrated under reduced pressure. Theresidue is partitioned between a suitable organic and basic aqueousphase, such as chloroform/methanol and aqueous sodium carbonate. Theorganic phase may be concentrated and the resulting compound (d)purified by standard methods such as flash chromatography. Ifchromatography is used, fractions containing product may be combined andconcentrated. The oil is dissolved in an appropriate solvent, such asdiethyl ether containing about 1% alcohol. A preferred alcohol ismethanol. The mixture may be treated with dry acid gas, such as dry HClgas to produce the corresponding acid addition salt of the desiredcompound (d).

One method for preparing Formula I compounds uses the Pictet-Spenglerreaction as represented by Scheme III. The substituents are as definedhereinabove. ##STR30##

Generally, the Scheme III reaction is carried out by reacting compound(e) with the selected aldehyde in a suitable solvent such as ethanol ormethanol for a period of about 1 to 50 hours depending on the desiredproduct. The reaction may be refluxed if necessary. The precipitatedreaction product is collected by common isolation methods, such asfiltration and may be purified by recrystallization. If a compound withan R₁ substituent is desired, the reaction may be followed by areductive alkylation. The reductive alkylation is represented by SchemeIV. ##STR31##

A protic acid and aldehyde solution is commonly added to an aqueoussolution of compound (f). The most preferred protic acid is formic acid.The most preferred aldehyde is formaldehyde. The artisan can readilychoose other appropriate reagents to facilitate the reductivealkylation. The resulting solution is refluxed for a period of about 4to 80 hours. After reflux the solution should be made basic using anappropriate base such as potassium carbonate. The desired product canthen be extracted with an appropriate organic phase, such as chloroform.The product can be dried, concentrated, and purified by known methodssuch as flash chromatography.

A preferred method for preparing certain Formula I compounds, wherein R₂is hydrogen, utilizes the modified Pictet-Spengler reaction describedsupra, as represented by Scheme V. The substituents are as definedhereinabove. ##STR32##

Compound (h) and compound (i) are contacted in a suitable protic aqueousacid solution. When compounds having hydrogen at the 1-position aredesired, glyoxylic acid may be used in place of (i). This step may becompleted under inert conditions. Compound (h) and compound (i) may berefluxed under atmospheric or inert conditions for a period of about 20to about 30 hours. Preferred protic acids include sulfuric acid andhydrochloric acid. The most preferred acid solution is 1N HCl. If directisolation is not effective, then the reaction mixture may be neutralizedwith an appropriate base, such as potassium carbonate, followed byextraction with an organic phase, such as chloroform. The product can beisolated through solvent removal followed by chromatographic isolation,such as silica gel chromatography, or other common isolation techniques.Typically the product is isolated as the acid addition salt. Appropriatesalt forms are discussed supra.

As noted above, the compounds of the present invention can exist asresolved enantiomers. The single (-)enantiomer may be prepared by thechemical resolution method of A. I. Meyers as represented by Scheme VIinfra. The (+)enantiomer may be prepared using known resolutiontechniques described supra. All substituents are as defined hereinabove.##STR33##

In Scheme VI, CSA represents camphorsulfonic acid. Butylformadine (l) isprepared from the amino acid valine using known methods. Other formadinecompounds will also work. In step 1, the compound (k) and butylformadine(l) solution is refluxed for a period of about 70 to 80 hours. Theproduct of the reflux reaction can be purified by standard isolationmethods, such as flash chromatography. The isolated oil can be usedwithout further purification.

Compound (m) prepared in step 1, can be added to a suspension ofpotassium hydride (KH) in tetrahydrofuran (THF).Tetramethylethylenediamine (TMEDA) and then chloromethylmethyl ether(MOMCl) are added to the solution, as represented by step 2. The mixtureis stirred for a period of about 1 hour. The mixture can be treated withwater and partitioned between an appropriate organic, such as diethylether, and water. The product should be extracted with the organicphase, dried over potassium carbonate, and concentrated. The resultingoil may be used in subsequent steps without further purification.

In step 3, n-BuLi is slowly added dropwise to a stirred, cooled (about-76° C. to -80° C.) solution of the formadine in dry THF. The solutionis stirred for a period of about 1 hour followed by addition of thechloro compound in dry THF. The solution is stirred for an additionalperiod of about 4-5 hours at the reduced temperature. The mixture isallowed to cool to room temperature for a period of about 4 to 14 hours.Wet THF is added and the solution concentrated. The residue is dissolvedin an appropriate organic solvent such as chloroform and washed withwater. The organic phase is dried over a suitable drying agent, such assodium carbonate, and concentrated to facilitate purification of thedesired product. The product may be isolated by flash chromatography andconcentrated. The resulting oil may be used in subsequent steps withoutfurther purification.

The deprotection reaction represented in step 4 is begun at reducedtemperature (about 0° C.). Water, acetic acid, and hydrazine hydrate areadded to compound (o). The reaction temperature is decreased to about-10° C. to -20° C. for a period of about 60-120 hours. The mixture isallowed to warm to ambient temperature and is concentrated. The productis dissolved in an appropriate organic phase, such as chloroform, andwashed with water. The organic phase is dried over a suitable dryingagent, such as sodium carbonate, and concentrated to a viscous oil. Theoil is dissolved in an appropriate solvent, such as diethyl ether andtreated with a suitable organic or inorganic acid to afford the desiredacid addition salt. The salt can be isolated and purified by commonchemical methods.

If the desired product has an alkyl group at the R₃ position, thereaction represented by Scheme VII may be employed. ##STR34##

In Scheme VII, an appropriate saturated base solution, such as sodiumcarbonate, is added to compound (g). The desired compound (g) salt maybe prepared by the method of Scheme II, above. The mixture is stirred atabout ambient temperature for a period of about 1 hour. The layers areseparated, and the aqueous layer is extracted with an appropriateorganic solvent, such as chloroform. The organic layers are dried overan appropriate drying agent, such as sodium sulfate, and concentrated.The residue is dissolved in a suitable solvent such as toluene andtreated with phthalic anhydride. The solution is refluxed for a periodof about 12 to 20 hours with azeotropic drying. The solution is cooled,concentrated, and recrystallized to give compound (r).

In the next step, compound (r) is mixed in THF. A cooled (about 0° C.)suspension of an appropriate base, such as potassium hydride in dry THF,is slowly added to the compound (r) solution. After the addition of thethe base, the mixture is stirred for a period of about 1 hour.Tetramethylethylenediamine (TMEDA) is added, followed by a haloalkylsuch as methyl iodide (MeI). After about 1 hour, the reaction isquenched by the addition of water, followed by extraction with anappropriate organic phase, such as diethyl ether. The organic phases aredried over an appropriate drying agent, such as magnesium sulfate andconcentrated.

The solution of the concentrated compound (s) can be used directly inthe next step. It is contacted with an appropriate solvent, such asmethanol, and treated with hydrazine. The mixture is refluxed for aperiod of about 2 hours. The mixture is cooled to ambient temperatureand treated with concentrated acid, such as HCl. The mixture is thentreated with an alcohol and refluxed for a period of about 12 to 20hours. Preferred alcohols include methanol, ethanol, and butanol. Aftercooling to ambient temperature, the mixture is partitioned between asuitable organic and an aqueous phase. One suitable combination ischloroform and concentrated sodium carbonate solution. The aqueous layermay be further extracted, the organic phases combined, dried, andconcentrated. The product may be purified by flash chromatography,concentrated, and converted to a desired salt. The resulting compound(t) may be used in Scheme III or Scheme V to produce the desired FormulaI compound.

Compounds of Formulas XI and XII may be prepared using the methodsdescribed supra. However, a preferred method for preparing compounds ofFormula XI and XII is illustrated by Scheme VIII ##STR35## wherein R³²is independently selected from C₁ -C₆ alkyl; A, and Q' are definedsupra.

Further, compounds of Example 108 can be prepared as illustrated by thefollowing Scheme: ##STR36##

Similarly, compounds of Example 109 can be prepared as illustrated bythe following Scheme: ##STR37##

The following Examples further illustrate the preparation of certain ofthe Formula I, II, XI, and XII compounds. The examples are illustrativeonly, and are not intended to limit the scope of the invention.

The column chromatography procedures used standard flash chromatographytechniques. One well-known reference describing appropriate flashchromotagraphy techniques is Still, W. C. Kahn, and Mitra, J. Org. Chem.1978, 43, 2932. Fractions containing product were generally evaporatedunder reduced vacuum to provide the product.

Optical rotations were obtained using methanol, pyridine, or othersuitable solvent.

The hydrochloride salt of the particular compound was prepared byplacing the free base into diethyl ether containing an alcohol such asmethanol or other suitable solvent mixture. While stirring this ethersolution, a solution of HCl in diethyl ether was added dropwise untilthe solution became acidic. Alternatively, the ether solution wastreated with dry HCl gas.

The maleate salt of the particular compound was prepared by placing thefree base in ethyl acetate or other suitable solvent and treating withmaleic acid. The precipitate formed was filtered and dried to providethe corresponding hydrochloride or maleate salt of the free base.

Compounds of Formulas I through VI and VIII through XII are morepreferred for treating a mammal suffering from or susceptible to acondition associated with abnormal or dysfunctional 5-HT_(2B) receptorstimulation. Additionally, compounds of Formulas I through VI and VIIIthrough XII are more preferred for blocking a 5-HT_(2B) receptor in amammal or in vitro. Finally, compounds of Formulas I through VI and VIIIthrough XII are more preferred for use in an article of manufacture.##STR38##

For Examples 90 through 109, where applicable, diethyl ether wasdistilled from sodium benzophenone ketyl prior to use. All reactionswere performed under a positive pressure of argon. ¹ H-NMR and ¹³ C-NMRdata were recorded on a Bruker AC-200P (200 MHz). IR spectra wereobtained on Nicolet 510 P-FT (film and KBr). Melting points weredetermined on a Buchi apparatus and are not corrected. Analytical TLCwas performed on Merck TLC glass plates precoated with F₂₅₄ silica gel60 (UV, 254 nm and Iodine). Chromatographic separations were performedby using 230-400 mesh silica gel (Merck). N-BOC-aziridines (2a-d) wereprepared from the corresponding alkenes following standard procedures.

Preparation 1 Preparation of 4-chlorobutanal ##STR39##

4-Chlorobutyryl chloride (300 g, 2.13 mol.) was dissolved in dry THF (3L). To this solution was added 2,6-lutidine (252 mL) followed by 5% Pd/C(30 g). This mixture was placed in a Parr hydrogenator and shaken under60 psi of hydrogen for 6 hours. The mixture was purged with nitrogen,filtered, washing the catalyst with THF (500 mL), and concentrated atroom temperature under reduced pressure. Distillation afforded4-chlorobutanal (148.3 g) as a colorless liquid.

EXAMPLE 1 Preparation of 8-methyl-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole##STR40##

A solution of 3,4-dimethoxybenzaldehyde (24.5 g, 0.15 mol.),N-acetylglycine (17.4 g, 0.15 mol.) and sodium acetate (12.1 g, 0.15mol) in acetic anhydride (135 mL) was heated to 100° C. for 12 hours.The reaction mixture was cooled to ambient temperature poured onto ice(300 mL) with stirring. The product was isolated by filtration, washedwith water (3×50 mL) and diethyl ether (3×50 mL) and dried under reducedpressure (16.3 g). ##STR41##

A suspension of azalactone prepared above (1.35 g, 5.46 mmol.) and7-methyl-tryptamine hydrochloride (1.15 g, 5.46 mmol.) in 1N HCl (50 mL)was heated to reflux for 24 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic layers were concentrated under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (730 mg) byfiltration. (mp=168° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               66.36    66.15                                                H               6.24     6.28                                                 N               6.19     5.79                                                 ______________________________________                                    

EXAMPLE 2 Preparation of 8-bromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

To a stirred suspension of 2-bromophenyl-hydrazine hydrochloride (25.8g, 115 mmol.) in chloroform (500 mL) was added saturated sodiumcarbonate solution (500 mL). The mixture was stirred for 30 minutes andextracted with chloroform (2×200 mL). The combined organic phases wereconcentrated to afford the hydrazine free base as a yellow oil. This oilwas dissolved in methanol (100 mL) and treated slowly with4-chlorobutanal (12.3 g, 115 mmol). The mixture was placed in a sealabletube and purged with nitrogen for 10 minutes. The tube was sealed andplaced in an oil bath preheated to 95° C. Heating was continued for 18hours. The resulting dark solution was cooled to ambient temperature andconcentrated under reduced pressure. The residue was partitioned betweenchloroform/methanol (75/25 by volume) and aqueous sodium carbonatesolution. The organic phase was concentrated and the crude indoleethanamine was purified by flash chromatography on silica gel (0-25%methanol gradient in chloroform as eluent). Fractions containing productwere combined and concentrated. The oil was dissolved in diethyl ether(300 mL) containing 1% methanol and treated with dry HCl gas. Thehydrochloride salt was isolated by filtration, washed with 2-propanol(50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptaminehydrochloride (3.6 g) as a pale solid, which was used without furtherpurification.

A suspension of azalactone (prepared as described in Example 1) (1.16 g,4.7 mmol.) and 7-bromotryptamine hydrochloride (1.0 g, 3.6 mmol.) in 1NHCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The brown solid was trituratedwith isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50mL). Recrystallization from ethanol afforded 860 mg of desired productas the hydrochloride salt. (mp=279°-281° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               54.87    54.75                                                H               5.07     5.20                                                 N               6.40     6.23                                                 ______________________________________                                    

EXAMPLE 3 Preparation of 6,8-dibromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole

To a stirred, cooled (-5° C.) solution of 2,4-dibromoaniline (50.0 g,0.2 mol.) in concentrated HCl solution (110 mL) was added sodium nitrite(13.8 g, 0.2 mol.) in water (110 mL) dropwise at such a rate as tomaintain temperature below 5° C. After complete addition, the mixturewas further stirred at 5° C. for 30 minutes. A solution of tin chloridemonohydrate (135.4 g, 0.6 mol.) in concentrated HCl (total volume 170mL) was added dropwise again maintaining temperature below 5° C. Aftercomplete addition and 30 minutes of further stirring, the mixture wasplaced in the freezer overnight. The light brown solid whichprecipitated was isolated by filtration and washed with cold brinefollowed by a solution of petroleum ether/diethyl ether (2/1 by volume).This solid was slowly added to an ice cooled mixture of 50% sodiumhydroxide solution/ethyl acetate. The mixture was extracted with ethylacetate and the organic phase dried over magnesium sulfate. Afterfiltration, the solution was concentrated to 400 mL total volume,diluted with diethyl ether (1.5 L) and treated with dry HCl. Theproduct, 2,4-dibromophenyl-hydrazine hydrochloride (45.9 g) was isolatedas a white solid and used without further purification.

To a stirred suspension of 2,4-dibromophenylhydrazine hydrochloride(22.0 g, 83 mmol.) in chloroform (500 mL) was added saturated potassiumcarbonate solution (500 mL). The mixture was stirred for 30 minutes andextracted with chloroform (2×200 mL). The combined organic phases wereconcentrated to afford the hydrazine free base as a yellow oil. This oilwas dissolved in methanol (163 mL) and treated slowly with4-chlorobutanal (8.8 g, 83 mmol.). The mixture was placed in a sealabletube and purged with nitrogen for 10 minutes. The tube was sealed andplaced in an oil bath preheated to 95° C. Heating was continued for 18hours. The resulting dark solution was cooled to ambient temperature andconcentrated under reduced pressure. The residue was partitioned betweenchloroform/methanol (75/25 by volume) and aqueous sodium carbonatesolution. The organic phase was concentrated and the crude indoleethanamine was purified by flash chromatography on silica gel (0-25%methanol gradient in chloroform as eluent). Fractions containing productwere combined and concentrated. The oil was dissolved in diethyl ether(300 mL) containing 1% methanol and treated with dry HCl gas. Thehydrochloride salt was isolated by filtration, washed with 2-propanol(50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptaminehydrochloride (1.5 g) as a pale solid, which was used without furtherpurification.

A suspension of azalactone (prepared as described in Example 1) (0.45 g,1.82 mmol.) and 5,7-dibromotryptamine hydrochloride (0.58 g, 1.64 mmol.)in 1N HCl (65 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic layers were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (340 mg) byfiltration. (mp=177°-179° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               48.34    48.61                                                H               4.06     4.17                                                 N               4.70     4.69                                                 ______________________________________                                    

EXAMPLE 4 Preparation of 6-methyl-8-bromo-1- (3,4-dimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole hydrochloride

To a stirred, cooled (-5° C.) solution of 2-bromo-4-methylaniline (50.54g, 0.272 mol.) in concentrated HCl solution (200 mL) was added sodiumnitrite (18.9 g, 0.274 mol.) in water (200 mL) dropwise at such a rateas to maintain temperature below 5° C. After complete addition, themixture was further stirred at 5° C. for 30 minutes. A solution of tinchloride monohydrate (185.4 g, 0.822 mol.) in concentrated HCl (totalvolume 400 mL) was added dropwise again maintaining temperature below 5°C. After complete addition and 30 minutes of further stirring, themixture was placed in the freezer overnight. The light brown solid whichprecipitated was isolated by filtration and washed with cold brinefollowed by a solution of petroleum ether/diethyl ether (2/1 by volume).This solid was slowly added to an ice cooled mixture of 50% sodiumhydroxide solution/ethyl acetate. The mixture was extracted with ethylacetate and the organic phase dried over magnesium sulfate. Afterfiltration, the solution was concentrated to 400 mL total volume,diluted with diethyl ether (1.5 L) and treated with dry HCl. Theproduct, 2-bromo-4-methylphenylhydrazine hydrochloride (52.4 g) wasisolated as a light brown solid and used without further purification.

5-Methyl-7-bromotryptamine hydrochloride (4.95 g) was prepared asdescribed in Example 3, except using 2-bromo-4-methylphenyl hydrazinchydrochloride (21 g) as starting material.

A suspension of azalactone (prepared as described in Example 5) (1.44 g,6.07 mmol.) and 5-methyl-7-bromotryptamine hydrochloride (1.12 g, 3.87mmol.) in 1N HCl (80 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and the crude product isolated by filtration. The brownsolid was triturated with isopropyl alcohol (3×50 mL) and washed withdiethyl ether (3×50 mL). Recrystallization from ethanol afforded 1.06 gof desired product as a pale solid. (mp=251°-253° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               55.83    56.08                                                H               5.35     5.32                                                 N               6.20     6.33                                                 ______________________________________                                    

EXAMPLE 5 Preparation of 8-methoxy-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole

To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazinehydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added4-chlorobutanal (9.0 g, 84 mmol.) followed by dropwise addition oftriethylamine (8.6 g, 85 mmol.) in THF (20 mL) Upon complete addition,the cooling bath was removed and the solution stirred for 1 hour. Thereaction mixture was filtered and the filter cake washed with THF (100mL). The combined filtrates were concentrated to an orange oil, whichwas dissolved in methanol (150 mL) and water (5 mL). The solution wastransferred to a sealable tube and purged with nitrogen for 10 minutes.The tube was sealed and placed in an oilbath preheated to 95° C. Afterheating for 14 hours, the reaction mixture was cooled to ambienttemperature and concentrated under reduced pressure. The residue waspartitioned between saturated aqueous potassium carbonate and 3:1chloroform:2-propanol. The organic phase was dried over sodium sulfateand concentrated. The residue was purified by flash chromatography onsilica gel (15% methanol, 0.2% NH₄ OH, in chloroform as eluent). Thefractions containing product were pooled and concentrated under reducedpressure. The residue was dissolved in methanol and treated with dry HCland concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) asa stable foam, which was used without further purification.

A suspension of azalactone (prepared as described in Example 1) (1.20 g,4.85 mmol.) and 7-methoxytryptamine hydrochloride (1.0 g, 4.4 mmol.) in1N HCl (120 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic layers were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (770 mg) byfiltration. (mp=219°-220° C., dec.).

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               64.09    64.04                                                H               6.02     6.18                                                 N               5.98     5.93                                                 ______________________________________                                    

EXAMPLE 6 Preparation of 6,8-difluoro-1-(3,4-dimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole##STR42##

To a stirred suspension of 2,4-difluorophenylhydrazine hydrochloride(18.5 g, 128 mmol.) in chloroform (500 mL) was added saturated potassiumcarbonate solution (500 mL). The mixture was stirred for 30 minutes andextracted with chloroform (2×200 mL). The combined organic phases wereconcentrated to afford the hydrazine free base as a yellow oil. This oilwas dissolved in a solution of methanol (163 mL), water (36 mL) andsodium acetate (10.57 g) and treated slowly with 4-chlorobutanal (13.7g, 128 mmol.). The mixture was placed in a sealable tube and purged withnitrogen for 10 minutes. The tube was sealed and placed in an oil bathpreheated to 95° C. Heating was continued for 15 hours. The resultingdark solution was cooled to ambient temperature and concentrated underreduced pressure. The residue was partitioned betweenchloroform/methanol (75/25 by volume) and aqueous sodium carbonatesolution. The organic phase was concentrated and the crude indoleethanamine was purified by flash chromatography on silica gel (0-25%methanol gradient in chloroform as eluent). Fractions containing productwere combined and concentrated. The oil was dissolved in diethyl ether(300 mL) containing 1% methanol and treated with dry HCl gas. Thehydrochloride salt was isolated by filtration, washed with 2-propanol(50 mL) and diethyl ether (100 mL) and dried to afford 7-bromotryptaminehydrochloride (6.3 g) as a pale solid, which was used without furtherpurification. ##STR43##

A suspension of azalactone (prepared as described in Example 1) (1.07 g,4.33 mmol.) and 5,7-difluorotryptamine hydrochloride (1.0 g, 4.3 mmol.)in 1N HCl (70 mL) was heated to reflux for 65 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic layers were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (450 mg) byfiltration. (mp=164°-166° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               60.76    60.63                                                H               5.10     5.14                                                 N               5.90     5.82                                                 ______________________________________                                    

EXAMPLE 7 Preparation of 7-methyl-8-bromo-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared asdescribed for 2-bromo-4-methylphenylhydrazine hydrochloride in Example4, except using 2-bromo-3-methylaniline as starting material.

6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 4,except using 2-bromo-3-methylphenylhydrazine hydrochloride as startingmaterial.

A suspension of azalactone (prepared as described in Example 1) (3.63 g,14.7 mmol.) and 6-methyl-7-bromotryptamine hydrochloride (4.25 g, 4.21mmol.) in 1N HCl (150 mL) was heated to reflux for 18 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with dry HCl. The product was isolated as the hydrochloride salt(3.11 g) by filtration. m/e=414.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               55.83    56.13                                                H               5.18     5.29                                                 N               6.20     6.31                                                 ______________________________________                                    

EXAMPLE 8 Preparation of 6-(1,1-dimethylethyl)-1-(3,4-dimethoxyphenyl)methyl!1,2,3,4-tetrahydro-1-9H-pyrido- 3,4b!indolehydrochloride

5-(1,1-dimethylethyl)-tryptamine hydrochloride was prepared (2.95 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 4,except using 4-(1,1-dimethylethyl)-phenylhydrazine hydrochloride (6.00g) as starting material.

A suspension of azalactone (prepared as described in Example 1) (1.25 g,5.26 mmol.) and 5-(1,1-dimethylethyl)-tryptamine hydrochloride (1.33 g,5.26 mmol.) in 1N HCl (50 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, and the crude product isolated by filtration. The brownsolid was triturated with isopropyl alcohol (3×50 mL) and washed withdiethyl ether (3×50 mL). Recrystallization from ethanol afforded 0.74 gof desired product as a pale solid.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               69.47    69.66                                                H               7.53     7.50                                                 N               6.75     6.71                                                 ______________________________________                                    

EXAMPLE 9 Preparation of 5-fluoro-6-methyl-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole

3-Fluoro-4-methylphenylhydrazine hydrochloride (21.4 g) was prepared asdescribed for 2-bromo-4 methylphenylhydrazine hydrochloride in Example4, except using 3-fluoro-4-methylaniline as starting material.

4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 4,except using 3-fluoro-4-methylphenylhydrazine hydrochloride (6.00 g) asstarting material.

A suspension of azalactone (prepared as described in Example 1) (0.76 g,3.06 mmol.) and 4-fluoro-5-methyltryptamine hydrochloride (0.70 g, 3.06mmol.) in 1N HCl (40 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with maleic acid. The product was isolated as the maleate salt(60 mg) by filtration. mp. 191°-194° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               63.82    63.60                                                H               5.78     5.65                                                 N               5.95     5.92                                                 ______________________________________                                    

EXAMPLE 10 Preparation of 7,8,9,10-tetrahydro-10-(3,4-dimethoxyphenyl)methyl!-11H-benzo g!pyrido 3,4-b!indole

6,7-Benzotryptamine hydrochloride was prepared (2.85 g) as described for5-methyl-7-bromotryptamine hydrochloride in Example 4, except using1-naphthyl-hydrazine hydrochloride (6.00 g) as starting material.

A suspension of azalactone (prepared as described in Example 1) (1.51 g,6.11 mmol.) and 6,7-benzotryptamine hydrochloride (1.50 g, 6.11 mmol.)in 1N HCl (40 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic layers were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (240 mg) byfiltration. m/e=373, mp. 187° C. (dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               68.84    68.63                                                H               5.78     5.91                                                 N               5.73     5.67                                                 ______________________________________                                    

EXAMPLE 11 Preparation of 6-cyclohexyl-1-(3,4-dimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

4-Cyclohexylphenylhydrazine hydrochloride (35.6 g) was prepared asdescribed for 2-bromo-4-methylphenylhydrazine hydrochloride in Example4, except using 4-cyclohexylaniline as starting material.

5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using4-cyclohexylphenylhydrazine hydrochloride as starting material.

A suspension of azalactone (prepared as described in Example 1) (0.54 g,2.18 mmol.) and 5-cyclohexyltryptamine hydrochloride (0.6 g, 2.18 mmol.)in 1N HCl (30 mL) was heated to reflux for 14 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic layers were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (140 mg) byfiltration. m/e=404.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               69.21    69.17                                                H               6.97     7.01                                                 N               5.38     5.53                                                 ______________________________________                                    

EXAMPLE 12 Preparation of 5,8-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido3,4b!indole hydrochloride

4,7-dimethyltryptamine hydrochloride was prepared (0.94 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using2,5-dimethylphenylhydrazine hydrochloride (16.8 g) as starting material.

A suspension of azalactone (prepared as described in Example 1) (1.04 g,4.21 mmol.) and 4,7-dimethyltryptamine hydrochloride (0.94 g, 4.21mmol.) in 1N HCl (40 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with anhydrous HCl. The product was isolated as thehydrochloride salt (370 mg) by filtration. m/e=349

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               68.29    68.59                                                H               7.03     6.92                                                 N               7.24     7.04                                                 ______________________________________                                    

EXAMPLE 13 Preparation of 6-(1-methylethyl)-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4b!indole

To a stirred suspension of 4-isopropylphenylhydrazine hydrochloridemonohydrate (15.3 g, 91.95 mmol.) in chloroform (250 mL) was addedsaturated sodium carbonate solution (250 mL). The mixture was stirredfor 30 minutes and extracted with chloroform (2×200 mL). The combinedorganic phases were concentrated to afford the hydrazine free base as ayellow oil. This oil was dissolved in methanol (200 mL) and water (5 mL)and treated with sodium acetate (6.72 g, 82 mmol.) and 4-chlorobutanal(8.7 g, 82 mmol.). The mixture was placed in a sealable tube and purgedwith nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 100° C. Heating was continued for 18 hours. Theresulting dark solution was cooled to ambient temperature andconcentrated under reduced pressure. The residue was partitioned betweenchloroform/methanol (75/25 by volume) and aqueous sodium carbonatesolution. The organic phase was concentrated and the crude indoleethanamine was purified by flash chromatography on silica gel (0-25%methanol gradient in chloroform as eluent). Fractions containing productwere combined and concentrated. The oil was dissolved in diethyl ether(300 mL) containing 1% methanol and treated with dry HCl gas. Thehydrochloride salt was isolated by filtration, washed with 2-propanol(50 mL) and diethyl ether (100 mL) and dried to afford5-isopropyltryptamine hydrochloride (9.8 g) as a pale solid, which wasused without further purification.

A suspension of azalactone (prepared as described in Example 1) (1.55 g,6.31 mmol.) and 5-isopropyltryptamine hydrochloride (1.76 g, 7.37 mmol.)in 1N HCl (40 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic layers were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (310 mg) byfiltration. m/e=365, mp. 196°-200° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.48    67.74                                                H               6.71     6.75                                                 N               5.83     5.92                                                 ______________________________________                                    

EXAMPLE 14 Preparation of 6,8-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido3,4b!indole hydrochloride

5,7-Dimethyltryptamine hydrochloride was prepared (2.86 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using2,4-dimethylphenylhydrazine hydrochloride (15.0 g) as starting material.

A suspension of azalactone (prepared as described in Example 1) (1.65 g,6.67 mmol.) and 5,7-dimethyltryptamine hydrochloride (1.50 g, 6.67mmol.) in 1N HCl (70 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and the crude product isolated by filtration. The solid wastriturated with ethanol/hexanes (3×50 mL) and washed with hexanes (3×50mL). The product was isolated by filtration (820 mg). m/e=350.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               68.29    68.07                                                H               7.03     7.12                                                 N               7.24     7.23                                                 ______________________________________                                    

EXAMPLE 15 Preparation of 5,7-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido3,4b!indole hydrochloride

4,6-Dimethyltryptamine hydrochloride was prepared (1.06 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using3,5-dimethylphenylhydrazine hydrochloride (7.65 g) as starting material.

A suspension of azalactone (prepared as described in Example 1) (1.16 g,4.69 mmol.) and 4,6-dimethyltryptamine hydrochloride (1.05 g, 4.67mmol.) in 1N HCl (60 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and the crude product isolated by filtration. The solid wastriturated with ethanol/hexanes (3×50 mL) and washed with hexanes (3×50mL). The product was isolated by filtration (770 mg). m/e=350.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               68.29    68.09                                                H               7.03     7.12                                                 N               7.24     7.02                                                 ______________________________________                                    

EXAMPLE 16 Preparation of 6,7-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido3,4b!indole

To a stirred, cooled (0° C.) solution of 5,6-dimethyl-indole (3.69 g,25.4 mmol.) in dry diethyl ether (75 mL) was added dropwise oxalylchloride (3.8 mL, 43.0 mmol.) over 2 minutes. After further stirring for30 minutes, the bright yellow acid chloride (5.99 g) was isolated byfiltration and washed with dry diethyl ether. This acid chloride wasadded in portions to a rapidly stirred solution of aqueous (30%)ammonium hydroxide (100 mL). After the addition was complete, themixture was further stirred at ambient temperature for 30 minutes andthe crude product isolated by filtration. Recrystallization fromTHF/diethyl ether afforded product (3.05 g) as a tan solid.

To a stirred, refluxing solution of amide (prepared above) (3.05 g, 14.1mmol.) in THF was added dropwise a suspension of lithium aluminumhydride (3.07 g, 81.3 mmol.) in THF over 1 H. Upon complete addition,the mixture was further heated to reflux for 14 H. The reaction mixturewas cooled to 0° C. and carefully treated with water (3.1 mL) followedby 15% sodium hydroxide solution (3.1 mL), followed by water (9.3 mL).The salts were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was dissolved in diethyl ether (80mL) with 5% ethyl acetate and treated with anhydrous HCl. Thehydrochloride salt (2.65 g) was isolated by filtration and washed withdry ether.

A suspension of azalactone (prepared as described in Example 1) (1.10 g,4.45 mmol.) and 5,6-dimethyltryptamine hydrochloride (1.00 g, 4.45mmol.) in 1N HCl (60 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with maleic acid. The product was isolated as the maleate salt(450 mg) by filtration. mp. 197°-200° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               66.94    67.01                                                H               6.48     6.56                                                 N               6.00     5.98                                                 ______________________________________                                    

EXAMPLE 17 Preparation of 6-ethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4b!indole

To a stirred, cooled (0° C.) solution of 5-ethylindole (4.0 g, 27.5mmol.) in dry diethyl ether (250 mL) was added dropwise oxalyl chloride(4.8 mL, 55.1 mmol.) over 2 minutes. After further stirring for 30minutes, the bright yellow acid chloride was isolated by filtration andwashed with dry diethyl ether. This acid chloride was added in portionsto a rapidly stirred solution of aqueous (30%) ammonium hydroxide (200mL). After the addition was complete, the mixture was further stirred atambient temperature for 30 minutes and the crude product isolated byfiltration (4.7 g) as a tan solid.

To a stirred, refluxing solution of amide (prepared above) (4.7 g, 21.7mmol.) in THF was added dropwise a suspension of lithium aluminumhydride (4.7 g, 121 mmol.) in THF over 1 H. Upon complete addition, themixture was further heated to reflux for 14 H. The reaction mixture wascooled to 0° C. and carefully treated with water (4.7 mL) followed by15% sodium hydroxide solution (4.7 mL), followed by water (14.1 mL). Thesalts were removed by filtration and the filtrate was concentrated underreduced pressure. The residue was dissolved in diethyl ether (80 mL)with 5% ethyl acetate and treated with anhydrous HCl. The hydrochloridesalt (4.02 g) was isolated by filtration and washed with dry ether.

A suspension of azalactone (prepared as described in Example 1) (1.10 g,4.45 mmol.) and 5,6-dimethyltryptamine hydrochloride (1.00 g, 4.45mmol.) in 1N HCl (60 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with maleic acid. The product was isolated as the maleate salt(520 mg) by filtration. mp. 185° C. (dec.).

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               66.94    66.95                                                H               6.48     6.55                                                 N               6.01     5.99                                                 ______________________________________                                    

EXAMPLE 18 Preparation of 6-bromo-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4b!indole

A suspension of azalactone (prepared as described in Example 1) (0.91 g,3.7 mmol.) and 5-bromotryptamine hydrochloride (1.01 g, 3.7 mmol.) in 1NHCl (60 mL) was heated to reflux for 18 hours under nitrogen atmosphere.The reaction mixture was cooled to ambient temperature, neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic layers were concentrated under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (800 mg) byfiltration. (mp=184°-188° C., dec.) m/e=403.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               55.72    55.51                                                H               4.87     5.09                                                 N               5.41     5.36                                                 ______________________________________                                    

EXAMPLE 19 Preparation of 7,8-dimethyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido3,4b!indole hydrochloride

6,7-Dimethyltryptamine hydrochloride was prepared (2.26 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using2,2-dimethylphenylhydrazine hydrochloride (15.0 g) as starting material.

A suspension of azalactone (prepared as described in Example 1) (1.39 g,5.62 mmol.) and 6,7-dimethyltryptamine hydrochloride (1.26 g, 5.61mmol.) in 1N HCl (70 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with anhydrous HCl. The product was isolated as thehydrochloride salt (290 mg) by filtration. m/e=350

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               68.29    68.51                                                H               7.03     6.87                                                 N               7.24     7.22                                                 ______________________________________                                    

EXAMPLE 20 Preparation of 6-methyl-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido 3,4b!indole hydrochloride

A suspension of azalactone (prepared as described in Example 1) (3.4 g,12.4 mmol.) and 5-methyltryptamine hydrochloride (2.0 g, 9.9 mmol.) in1N HCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The solid was triturated withethanol and washed with diethyl ether. The product was isolated as thehydrochloride salt by filtration (3.2 g). mp. 245°-246° C. (dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.64    67.42                                                H               6.67     6.66                                                 N               7.51     7.25                                                 ______________________________________                                    

EXAMPLE 21 Preparation of 6-methyl-1-(3,4,5-trimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indolehydrochloride

A solution of 3,4,5-trimethoxybenzaldehyde (20.0 g, 0.10 mol.),N-acetylglycine (11.9 g, 0.10 mol.) and sodium acetate (8.4 g, 0.1 mol)in acetic anhydride (100 mL) was heated to 100° C. for 2 hours. Thereaction mixture was cooled to ambient temperature poured onto ice (300mL) with stirring. The product was isolated by filtration, washed withwater (3×50 mL) and diethyl ether (3×50 mL) and dried under reducedpressure (5.6 g).

A suspension of azalactone (prepared above) (2.0 g, 7.2 mmol.) and5-methyltryptamine hydrochloride (1.1 g, 5.4 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with isopropanol andwashed with diethyl ether. The product was isolated by filtration (650mg). mp. 228°-229° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               65.58    65.38                                                H               6.75     6.76                                                 N               6.95     6.92                                                 ______________________________________                                    

EXAMPLE 22 Preparation of 6-methyl-1-(2,3,4-trimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indolehydrochloride

Azalactone (12.28 g) was prepared as in Example 21 except using2,3,4-trimethoxybenzaldehyde (20.0 g).

A suspension of azalactone (prepared above) (2.0 g, 7.2 mmol.) and5-methyltryptamine hydrochloride (1.1 g, 5.4 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with isopropanol andwashed with diethyl ether The product was isolated by filtration (1.36g). mp. 214.5° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               65.58    65.41                                                H               6.75     6.70                                                 N               6.95     6.89                                                 ______________________________________                                    

EXAMPLE 23 Preparation of 6-methyl-1-(2-methoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

Azalactone (16.42 g) was prepared as in Example 21 except using2-methoxybenzaldehyde (20.0 g).

A suspension of azalactone (prepared above) (2.0 g, 9.2 mmol.) and5-methyltryptamine hydrochloride (1.5 g, 6.9 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with isopropanol andwashed with diethyl ether. The product was isolated by filtration (880mg). mp. 252.8° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               70.06    70.15                                                H               6.76     6.83                                                 N               8.17     8.16                                                 ______________________________________                                    

EXAMPLE 24 Preparation of 6-methyl-1-(2,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

Azalactone (7.55 g) was prepared as in Example 21 except using2,4-dimethoxybenzaldehyde (20.0 g).

A suspension of azalactone (prepared above) (2.0 g, 8.1 mmol.) and5-methyltryptamine hydrochloride (1.3 g, 6.1 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature, neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic layers were concentrated under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withanhydrous HCl. The product was isolated as the hydrochloride salt (361mg) by filtration. mp. 262.6° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.64    67.73                                                H               6.76     6.85                                                 N               7.51     7.50                                                 ______________________________________                                    

EXAMPLE 25 Preparation of 6-methyl-1-(2,5-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

Azalactone (13.21 g) was prepared as in Example 21 except using2,5-dimethoxybenzaldehyde (20.0 g).

A suspension of azalactone (prepared above) (2.0 g, 8.1 mmol.) and5-methyltryptamine hydrochloride (1.3 g, 6.1 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature, neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic layers were concentrated under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withanhydrous HCl. The product was isolated as the hydrochloride salt (1.14g) by filtration. mp. 262° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.64    67.36                                                H               6.76     6.71                                                 N               7.51     7.25                                                 ______________________________________                                    

EXAMPLE 26 Preparation of 6-methyl-1-(2,4,5-trimethoxyphenyl)-methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indolehydrochloride

Azalactone (8.36 g) was prepared as in Example 21 except using2,4,5-trimethoxybenzaldehyde (20.0 g).

A suspension of azalactone (prepared above) (2.0 g, 7.2 mmol.) and5-methyltryptamine hydrochloride (1.1 g, 5.4 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with isopropanol andwashed with diethyl ether. The product was isolated by filtration.Recrystallization from ethanol/cyclohexane afforded product (299 mg).mp. 176.3° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               65.58    65.51                                                H               6.75     6.73                                                 N               6.95     6.87                                                 ______________________________________                                    

EXAMPLE 27 Preparation of 6-(1-methylethyl)-1-(2,3,4-trimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

A suspension of azalactone (prepared as in Example 22) (1.0 g, 3.61mmol.) and 5-isopropyltryptamine hydrochloride (prepared as in Example13) (646 mg, 2.7 mmol.) in 1N HCl (20 mL) was heated to reflux for 48hours under nitrogen atmosphere. The reaction mixture was cooled toambient temperature, neutralized with saturated aqueous potassiumcarbonate solution and extracted with chloroform. The combined organiclayers were concentrated under reduced pressure and the residuechromatographed on silica gel (ethyl acetate/0.2% NH₄ OH as eluent). Thefractions containing product were pooled and concentrated under reducedpressure. The residue was dissolved in ethyl acetate containing 1%methanol and treated with anhydrous HCl. The product was isolated as thehydrochloride salt (315 mg) by filtration. mp. 147.3° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               66.89    66.80                                                H               7.25     7.01                                                 N               6.50     6.39                                                 ______________________________________                                    

EXAMPLE 28 Preparation of 6-methyl-1-(3,4-dimethoxy-5-nitrophenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

Azalactone (16.9 g) was prepared as in Example 21 except using3,4-dimethoxy-5-nitrobenzaldehyde (23.5 g).

A suspension of azalactone (prepared above) (2.8 g, 9.6 mmol.) and5-methyltryptamine hydrochloride (2.0 g, 9.5 mmol.) in 1N HCl (50 mL)was heated to reflux for 72 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with isopropanol andwashed with diethyl ether. The product was isolated as the hydrochloridesalt by filtration (3.44) mp. 239°-243° C., m/e=381.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               60.36    60.54                                                H               5.79     5.66                                                 N               10.06    10.12                                                ______________________________________                                    

EXAMPLE 29 Preparation of 6-methyl-1-(3-iodo-4,5-dimethoxy-phenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole

To a stirred, cooled (0° C.) solution of iodovanillin (10.0 g, 35.96mmol.) in dimethylformamide (50 mL) was added anhydrous potassiumcarbonate (20.0 g, 143.86 mmol.) followed by iodomethane (3.11 mL, 50.0mmol.). The mixture was allowed to warm to ambient temperature and stirfor 14 H. The mixture was poured into diethyl ether (500 mL) and washedwith water (3×150 mL). The organic phase was dried over MgSO₄ andconcentrated under reduced pressure to afford3-iodo-4,5-dimethoxybenzaldehyde (9.5 g) as a yellow oil whichsolidified upon standing and was used without further purification.

Azalactone (11.1 g) was prepared as in Example 21 except using3-iodo-4,5-dimethoxybenzaldehyde (9.5 g), and hippuric acid (6.41 g)instead of N-acetylglycine.

A suspension of azalactone (prepared above) (2.2 g, 5.0 mmol.) and5-methyltryptamine hydrochloride (1.0 g, 4.3 mmol.) in 1N HCl (100 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature, neutralized withsaturated aqueous sodium hydroxide solution and extracted withchloroform. The combined organic layers were concentrated under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (134 mg) byfiltration. m/e=463.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               51.92    52.15                                                H               4.71     4.72                                                 N               4.84     4.70                                                 ______________________________________                                    

EXAMPLE 30 Preparation of 6-methyl-1-(3,4-dimethoxy-5-amino-phenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole dihydrochloride

To a stirred solution of nitro compound (prepared in Example 28) (3.0 g,7.2 mmol.) in acetic acid (40 mL) was added activated zinc dust (4.64g). The reaction mixture was stirred at ambient temperature for 2 H,diluted with water (200 mL) and filtered through celite. The filtratewas neutralized with aqueous ammonium hydroxide solution and extractedwith chloroform. The organic phase was washed with brine and dried overmagnesium sulfate. The combined organic phases were concentrated underreduced pressure and the residue dissolved in ethyl acetate and treatedwith anhydrous HCl. The product was isolated by filtration, washing withdiethyl ether and trituration with ethyl acetate to afford product asthe bis-hydrochloride salt (2.41 g). mp. 230°-234° C., m/e=351.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               59.44    58.47                                                H               6.41     6.31                                                 N               9.90     9.68                                                 ______________________________________                                    

EXAMPLE 31 Preparation of 6-methyl-1-(3-methoxy-4-propoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole

To a stirred solution of vanillin (30.0 g, 197 mmol.) in methanol (100mL) was added anhydrous potassium carbonate (13.7 g, 99 mmol.) followedby allyl bromide (17.0 mL, 197 mmol.). The mixture was heated to refluxfor 5 H. The reaction mixture was filtered and concentrated underreduced pressure to afford the intermediate product (30.4 g) as an oilysolid which was used without further purification.

Azalactone (32.2 g) was prepared as in Example 21 except using3-methoxy-4-allyloxybenzaldehyde (30.4 g), and hippuric acid (28.3 g)instead of N-acetyl glycine.

A suspension of azalactone (prepared above) (1.74 g, 5.2 mmol.) and5-methyltryptamine hydrochloride (1.1 g, 5.2 mmol.) in 1N HCl (40 mL)and ethanol (30 mL) was heated to reflux for 18 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic phases were concentratedunder reduced pressure and the residue chromatographed on silica gel(ethyl acetate/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (560 mg) byfiltration. m/e=362. The product was used without further purification.

To a suspension of maleate salt (560 mg, 1.7 mmol.) in chloroform (100mL) was added saturated potassium carbonate solution (100 mL) withvigorous stirring. The layers were separated and the aqueous phase wasfurther extracted with chloroform (2×100 mL). The combined organicphases were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The free base was dissolved in ethanol andhydrogenated (25° C., 60 PSI) in the presence of raney nickel catalyst.The catalyst was removed by filtration and the solution concentratedunder reduced pressure to afford a viscous oil, which was dissolved inethyl acetate and treated with maleic acid (140 mg). The crude productwas isolated by filtration. Trituration with hot ethyl acetate andwashing with diethyl ether afforded product (170 mg) as the maleatesalt. mp. 188° C., m/e=365.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.48    67.62                                                H               6.71     6.66                                                 N               5.83     5.80                                                 ______________________________________                                    

EXAMPLE 32 Preparation of 6-methyl-1-(4-dimethylaminophenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indoledihydrochloride

To a stirred, cooled (-78° C.) suspension ofmethoxymethyltriphenylphosphonium chloride (13.79 g, 40.02 mmol.) in dryTHF (150 mL) was added n-BuLi solution (25.2 mL. 1.6M, 40.02 mmol.)dropwise by syringe. The orange suspension was stirred at -78° C. for 15min. A solution of 4-dimethylaminobenzaldehyde (5.00 g, 3.35 mmol.) inTHF (75 mL) was added to the ylide dropwise over 10 min. The reactionmixture was gradually warmed to ambient temperature and stirred 14 H.Saturated ammonium chloride solution (100 mL) was added and the mixtureextracted with diethyl ether (3×50 mL). The combined organic phases weredried over sodium sulfate and concentrated under reduced pressure.Chromatography on silica gel, eluting with 15% ethyl acetate/hexanesafforded product (4.70 g) as a mixture of olefin isomers which was usedwithout further purification.

A mixture of 5-methyltryptamine hydrochloride (891 mg, 4.23 mmol.) and1-methoxy-4'-dimethylaminostyrene (1.00 g, 5.64 mmol.) in acetonitrile(20 mL) and 1N HCl solution (150 mL) was heated to reflux for 96 H. Thereaction mixture was cooled to ambient temperature, neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic phases were concentrated under reducedpressure and the residue chromatographed on silica gel (2.5%MeOH/chloroform/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and treated with anhydrous HCl. The productwas isolated as the dihydrochloride salt (354 mg) by filtration. mp.275.4° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               64.28    64.21                                                H               6.94     7.01                                                 N               10.71    10.74                                                ______________________________________                                    

EXAMPLE 33 Preparation of 6-methyl-1-(4-dibutylaminophenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indoledihydrochloride

To a stirred, cooled (-78° C.) suspension ofmethoxymethyl-triphenylphosphonium chloride (8.81 g, 25.7 mmol.) in dryTHF (150 mL) was added n-BuLi solution (16.1 mL. 1.6M, 25.7 mmol.)dropwise by syringe. The orange suspension was stirred at -78° C. for 15min. A solution of 4-dibutylaminobenzaldehyde (5.00 g, 2.14 mmol.) inTHF (75 mL) was added to the ylide dropwise over 10 min. The reactionmixture was gradually warmed to ambient temperature and stirred 14 H.Saturated ammonium chloride solution (100 mL) was added and the mixtureextracted with diethyl ether (3×50 mL). The combined organic phases weredried over sodium sulfate and concentrated under reduced pressure.Chromatography on silica gel, eluting with 15% ethyl acetate/hexanesafforded product (3.47 g) as a mixture of olefin isomers which was usedwithout further purification.

A mixture of 5-methyltryptamine hydrochloride (605 mg, 2.87 mmol.) and1-methoxy-4'-dibutylamino-styrene (1.00 g, 3.83 mmol.) in acetonitrile(20 mL) and 1N HCl solution (150 mL) was heated to reflux for 96 H. Thereaction mixture was cooled to ambient temperature, neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic phases were concentrated under reducedpressure and the residue chromatographed on silica gel (2.5%MeOH/chloroform/0.2% NH₄ OH as eluent). The fractions containing productwere pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and treated with anhydrous HCl. The productwas isolated as the dihydrochloride salt (476 mg) by filtration. mp.266.6° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               68.05    67.92                                                H               8.25     8.22                                                 N               8.82     8.74                                                 ______________________________________                                    

EXAMPLE 34 Preparation of 6-methyl-1-(3-fluoro-4-methoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

Azalactone (0.330 g) was prepared as in Example 21 except using3-fluoro-4-methoxybenzaldehyde (5.0 g).

A suspension of azalactone prepared above (0.30 g, 1.3 mmol.) and5-methyltryptamine hydrochloride (0.27 g, 1.3 mmol.) in 1N HCl (20 mL)was heated to reflux for 24 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature neutralized withsaturated aqueous potassium carbonate solution and extracted withchloroform. The combined organic phases were concentrated under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withanhydrous HCl. The product was isolated as the hydrochloride salt (170mg) by filtration. m/e=324.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               66.57    66.37                                                H               6.15     6.16                                                 N               7.76     7.5                                                  ______________________________________                                    

EXAMPLE 35 Preparation of 6-methyl-1-(3,4-dimethylphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

Azalactone (11.3 g) was prepared as in Example 21 except using3,4-dimethylbenzaldehyde (25.0 g).

A suspension of azalactone prepared above (2.04 g, 9.5 mmol.) and5-methyl-tryptamine hydrochloride (2.0 g, 9.5 mmol.) in 1N HCl (80 mL)was heated to reflux for 24 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with ethanol and washedwith diethyl ether. The product was isolated as the hydrochloride saltby filtration (1.89 g). m/e=304.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               73.99    73.84                                                H               7.39     7.35                                                 N               8.21     8.48                                                 ______________________________________                                    

EXAMPLE 36 Preparation of 6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

Azalactone (5.26 g) was prepared as in Example 21 except using2-chloro-3,4-dimethoxybenzaldehyde (10.45 g).

A suspension of azalactone prepared above (1.34 g, 4.76 mmol.) and5-methyltryptamine hydrochloride (1.0 g, 4.75 mmol.) in 1N HCl (30 mL)was heated to reflux for 24 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with ethanol and washedwith diethyl ether. The product was isolated by filtration (1.19 g).m/e=370, mp. 244° C. (dec.).

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               61.92    61.67                                                H               5.94     5.94                                                 N               6.88     6.94                                                 ______________________________________                                    

EXAMPLE 37 Preparation of 6-methyl-1-(2-chloro-3-methoxy-4-hydroxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole hydrochloride

Azalactone (12.4 g) was prepared as in Example 21 except using2-chloro-3-methoxy-4-hydroxybenzaldehyde (12.0 g).

A suspension of azalactone prepared above (1.29 g, 4.82 mmol.) and5-methyl-tryptamine hydrochloride (1.0 g, 4.75 mmol.) in 1N HCl (30 mL)was heated to reflux for 24 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with ethanol and washedwith diethyl ether. The product was isolated by filtration (1.07 g). mp.240° C. (dec.).

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               61.07    60.83                                                H               5.64     5.71                                                 N               7.12     7.03                                                 ______________________________________                                    

EXAMPLE 38 Preparation of 5-fluoro-6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

A suspension of azalactone (prepared in Example 36) (2.15 g, 7.63 mmol.)and 4-fluoro-5-methyl-tryptamine hydrochloride (prepared in Example 9(1.0 g, 4.75 mmol.) in 1N HCl (80 mL) was heated to reflux for 24 hoursunder nitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and the crude product isolated by filtration. The solid wastriturated with ethanol and washed with diethyl ether. The product wasisolated as the hydrochloride salt by filtration (1.39 g). m/e=388.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               59.30    59.58                                                H               5.45     5.47                                                 N               6.59     6.71                                                 ______________________________________                                    

EXAMPLE 39 Preparation of6-methyl-1-(cyclohexylmethyl)-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indolehydrochloride

A suspension of cyclohexylacetaldehyde (631 mg, 5.0 mmol.) and5-methyltryptamine hydrochloride (1.0 g, 4.3 mmol.) in ethanol (20 mL)was heated to reflux for 36 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The solid was triturated with ethanol and washedwith diethyl ether. The product was isolated by filtration (731 mg).m/e=282, mp 230° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               71.56    71.27                                                H               8.53     8.56                                                 N               8.78     8.64                                                 ______________________________________                                    

EXAMPLE 40 Preparation of (±)6-methyl-1-(3,4-dimethoxyphenyl)-1-ethyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole(Z)-2-butenedioate

To a stirred, cooled (-20° C.) suspension ofmethoxymethyltriphenylphosphonium chloride (118.9 g, 347 mmol.) in dryTHF (2000 mL) was added potassium t-butoxide (39.3 g, 350 mmol.) inportions. The orange suspension was stirred at -20° C. for 30 min. Asolution of 3,4-dimethoxyacetophenone (50.0 g, 275 mmol.) in THF (500mL) was added to the ylide dropwise over 30 min. The reaction mixturewas gradually warmed to ambient temperature and stirred 2 H. Saturatedammonium chloride solution (500 mL) was added and the mixture extractedwith diethyl ether (3×500 mL). The combined organic phases were driedover sodium sulfate and concentrated under reduced pressure.Chromatography on silica gel, eluting with 15% ethyl acetate/hexanesafforded product (48.4 g) as a mixture of olefin isomers which was usedwithout further purification.

A mixture of 5-methyltryptamine hydrochloride (2.16 g, 10.3 mmol.) and1-methoxy-2-methyl-3',4'-dimethoxystyrene (prepared above) (2.13 g, 10.3mmol.) in methanol (12 mL) and 1N HCl solution (108 mL) was heated toreflux for 96 H. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The combined organic phases were concentratedunder reduced pressure and the residue chromatographed on silica gel(2.5% MeOH/chloroform/0.2% NH₄ OH as eluent). The fractions containingproduct (upper diastereomer) were pooled and concentrated under reducedpressure. The residue was dissolved in ethyl acetate and treated withmaleic acid. The product was isolated as the maleate salt (260 mg) byfiltration. mp. 187°-190° C.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               66.94    66.95                                                H               6.48     6.35                                                 N               6.00     5.81                                                 ______________________________________                                    

EXAMPLE 41 Preparation of (±)6,7-dimethyl-1-(3,4-dimethoxyphenyl)-1-ethyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole(Z)-2-butenedioate

5,6-dimethyltryptamine hydrochloride (prepared in Example 16) (1.60 g,7.12 mmol.) was converted to its free base with aqueous potassiumcarbonate in chloroform. This solution was dried and treated with1-methoxy-2-methyl-3',4'-dimethoxystyrene (prepared above in Example 40)(1.49 g, 7.14 mmol.) and trifluororacetic acid (1.62 g, 14.2 mmol) andwas heated to reflux for 96 H. The reaction mixture was cooled toambient temperature, neutralized with saturated aqueous potassiumcarbonate solution and extracted with chloroform. The combined organicphases were concentrated under reduced pressure and the residuechromatographed on silica gel (2.5% MeOH/chloroform/0.2% NH₄ OH aseluent). The fractions containing product (upper diastereomer) werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and treated with maleic acid. The product wasisolated as the maleate salt (560 mg) by filtration. m/e=364. mp. 177°C. (dec.).

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.48    67.34                                                H               6.71     6.68                                                 N               5.83     5.74                                                 ______________________________________                                    

EXAMPLE 42 Preparation of (±)6-ethyl-1-(3,4-dimethoxyphenyl)-1-ethyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole(Z)-2-butenedioate

5-ethyltryptamine hydrochloride (prepared in Example 17) (2.0 g, 8.9mmol.) was converted to its free base with aqueous potassium carbonatein chloroform. This solution was dried and treated with1-methoxy-2-methyl-3',4'-dimethoxystyrene (prepared above in Example 40)(1.86 g, 8.9 mmol.) and trifluroracetic acid (2.03 g, 17.8 mmol) and washeated to reflux for 96 H. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic phases wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (2.5% MeOH/chloroform/0.2% NH₄ OH as eluent). The fractionscontaining product (upper diastereomer) were pooled and concentratedunder reduced pressure. The residue was dissolved in ethyl acetate andtreated with maleic acid. The product was isolated as the maleate salt(430 mg) by filtration. m/e=364. mp. 192°-194° C. (dec.).

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.48    67.32                                                H               6.71     6.72                                                 N               5.83     5.76                                                 ______________________________________                                    

EXAMPLE 43 Preparation of (±)6-methyl-1-(3,4-dimethoxyphenyl)-1-propyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (Z)-2-butenedioate

To methanesulfonic acid (203 mL) was added phosphorus pentoxide (30.0 g)slowly with stirring. After the addition was complete, the mixture wasfurther stirred under nitrogen atmosphere for 2 hours until homogenous.To this solution was added 3,4-dimethoxyphenylacetonitrile (50 g, 0.28mol.) in a single portion, followed by 2-methyl-2,4-pentanediol (72.1mL, 0.56 mol.) dropwise at such a rate as to maintain a temperaturebetween 25° and 30° C. (1 hour). After complete addition, the reactionmixture was stirred at ambient temperature for 10 hours and poured ontoice (500 g). The mixture was made basic with sodium hydroxide solution(50%), added at such a rate as to keep the temperature below 35° C. Themixture was extracted with diethyl ether (3×250 mL) and the combinedorganic phases were dried over magnesium sulfate and concentrated underreduced pressure to afford a green solid. Distillation (Kugelrohr)afforded intermediate product (27.7 g) which was used without furtherpurification.

To a stirred, cool (-78° C.) solution of previously preparedintermediate product (27.2 g, 0.106 mol.) in THF (400 mL) under argonatmosphere was added n-butyllithium solution (68.7 mL, 1.6M in hexanes,0.11 mol.) dropwise via syringe over 15 minutes. After completeaddition, the orange solution was stirred at -78° C. for 30 minutes.Ethyl bromide (8.18 mL, 0.10 mol.) was added dropwise via syringe andthe resulting solution further stirred at -78° C. for 45 minutes.n-Butyllithium (68.7 mL, 1.6M in hexanes, 0.11 mol.) was added dropwiseover 15 minutes and the orange solution stirred for 2 hours. The mixturewas poured into ice/water (500 mL) and was acidified to pH 2-3 with 5NHCl solution. The mixture was extracted with diethyl ether (2×100 mL)and these extracts were discarded. The aqueous phase was made basic withsodium hydroxide solution (50%), cooling the mixture with ice whennecessary. The basic aqueous phase was extracted with diethyl ether(2×200 mL) and the combined organic extracts were dried over magnesiumsulfate, filtered and concentrated to afford product as an oily solid(12.08 g), which was used without further purification.

To a stirred cooled (-40° C.) solution of previous product (12.0 g, 39.3mmol.) in THF (90 mL) and ethyl alcohol (90 mL) was added 5N HClsolution until pH 7. In a separate flask, a solution of sodiumborohydride (2.12 g, 55.4 mmol.) was dissolved in water (20 mL) to which1 drop of 50% sodium hydroxide had been added. Portions of the sodiumborohydride solution and 5N HCl solution were alternately added to thereaction mixture such that the pH remained 6-8, at such a rate as tomaintain temperature between -35° and -45° C. After complete addition,the reaction mixture was warmed to ambient temperature over about 2hours. The reaction mixture was made basic with sodium hydroxidesolution and extracted with diethyl ether (3×100 mL). The combinedorganic phases were washed with brine and dried over magnesium sulfate.Filtration and removal of solvent afforded crude product (11.3 g) as aviscous oil, which was used without further purification.

A mixture of crude product from the previous reaction (11.3 g, 36.8mmol) and oxalic acid dihydrate (15.1 g, 120 mmol.) in water (300 mL)was heated to reflux for 12 hours. The mixture was cooled to ambienttemperature and extracted with chloroform (2×100 mL). The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated to afford aldehyde as an orange oil. Distillation(Kugelrohr) under reduced pressure afforded pure aldehyde (4.97 g) as apale oil.

A mixture of 5-methyltryptamine hydrochloride (2.53 g, 12.0 mmol.) and2-ethyl-3',4'-dimethoxyphenylacetaldehyde (prepared above) (2.49 g, 12.0mmol.) in ethanol(30 mL) was heated to reflux for 48 H. The reactionmixture was cooled to ambient temperature, neutralized with saturatedaqueous potassium carbonate solution and extracted with chloroform. Thecombined organic phases were concentrated under reduced pressure and theresidue chromatographed on silica gel (2.5% MeOH/chloroform/0.2% NH₄ OHas eluent). The fractions containing product (upper Rf diastereomer)were pooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and treated with maleic acid. The product wasisolated as the maleate salt (1.51 g) by filtration. m/e=364.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.48    67.35                                                H               6.71     6.96                                                 N               5.83     5.77                                                 ______________________________________                                    

EXAMPLE 44 Preparation of 2,6-dimethyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

An aqueous solution of 6-methyl-1-(2-chloro-3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride (Prepared in Example 36) (500 mg, 1.23 mmol.)was treated with sodium hydroxide (49 mg, 1.23 mmol.), followed byformic acid (0.91 mL) and aqueous formaldehyde solution (0.18 mL). Themixture was heated to reflux for 4 H. The reaction mixture was cooled toambient temperature and concentrated under reduced pressure. The residuewas partitioned between aqueous potassium carbonate solution and diethylether. The organic phase was dried over potassium carbonate andconcentrated under reduced pressure. The residue was dissolved in ethylacetate and treated with maleic acid. The maleate salt was isolated byfiltration and purified by recrystallization from ethyl acetate/hexanesto afford product (240 mg). m/e=385.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               62.34    62.47                                                H               5.84     5.71                                                 N               5.59     5.58                                                 ______________________________________                                    

EXAMPLE 45 Preparation of2-methyl-6-(1-methylethyl)-1,2,3,4-tetrahydro-1-(3,4-dimethoxyphenyl)methyl!-9H-pyrido- 3,4b!indole maleate

An aqueous solution of 6-(1-methylethyl)-1-(3,4-dimethoxyphenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole(Z)-2-butenedioate (prepared in Example 13) (500 mg, 1.04 mmol.) wastreated with sodium hydroxide (83 mg, 2.08 mmol.), followed by formicacid (0.77 mL) and aqueous formaldehyde solution (0.15 mL). The mixturewas heated to reflux for 4 H. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The combined organic layers wereconcentrated under reduced pressure and the residue chromatographed onsilica gel (ethyl acetate/0.2% NH₄ OH as eluent). The fractionscontaining product were pooled and concentrated under reduced pressure.The residue was dissolved in ethyl acetate containing 1% methanol andtreated with maleic acid. The product was isolated as the maleate salt(130 mg) by filtration. m/e=376.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.99    67.88                                                H               6.93     6.73                                                 N               5.66     5.69                                                 ______________________________________                                    

EXAMPLE 46 Preparation of (-)-(S)-6-methyl-1,2,3,4-tetrahydro-1-(3,4-dimethylphenyl)methyl!-9H-pyrido 3,4-b!indole hydrochloride

To a stirred solution of 6-methyl-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (3.14 g, 16.9 mmol.) in dry xylenes (65 mL) was added(S)-N,N-dimethyl-N'-(1-tert-butoxy-3-methyl)-2-butylformamidine (3.79 g, 17.7 mmol.) followed by camphorsulfonic acid (200 mg). The resultingsolution was heated to reflux for 72 hours. The solution was cooled toambient temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (1:3:6triethylamine:ethyl acetate:hexanes as eluent). The product containingfractions were pooled and concentrated to afford the product formamidine(5.99 g) as a viscous oil which was used without further purification.

To a stirred, cooled (0° C.) suspension of potassium hydride (25% oildispersion, 829 mg, 20.2 mmol.) in THF (10 mL) was added formamidineprepared above (5.99 g , 16.8 mmol.) in THF (45 mL). To this mixture wasadded tetramethylethylenediamine (3.0 mL, 20.2 mmol.) followed bychloromethylmethyl ether (1.9 mL, 25.2 mmol.). The mixture was stirredfor an additional 1 hour and treated with water (50 mL). The mixture waspartitioned between diethyl ether and water and the layers separated.The aqueous phase was extracted with diethyl ether (2×100 mL) and theorganic phases combined, dried over potassium carbonate, andconcentrated to afford product (6.73 g) as an orange oil, which was usedwithout further purification.

To a stirred, cooled (-78° C.) solution of previously preparedformamidine (6.29 g, 8.4 mmol.) in dry THF (100 mL) was added n-BuLi(1.7M solution in hexanes, 10.1 mL, 17.1 mmol.) dropwise over 5 minutes.The solution was further stirred at -78° C. solution for 1 hour andtreated with 1-chloromethyl-3,4-dimethoxybenzene (3.35 g, 17.9 mmol.) indry THF (15 mL). The solution was further stirred for 4 hours at -78° C.and allowed to warm to room temperature overnight. Wet THF was added (50mL) and the solution was concentrated under reduced pressure. Theresidue was dissolved in chloroform and washed with water. The organicphase was dried over sodium carbonate and concentrated. The crudeproduct was purified by flash chromatography on silica gel (1:3:6triethylamine:ethyl acetate:hexanes as eluent). The product containingfractions (upper Rf) were pooled and concentrated to afford product(3.92 g) as a viscous oil (m/e=550) which was used without furtherpurification.

To a stirred solution of methoxymethylindole prepared above (3.92 g ,7.13 mmol.) in THF (70 mL) was added 2N HCl (20 mL). The mixture wasstirred at ambient temperature for 24 hours, and partitioned betweendiethyl ether and water. The aqueous phase was back extracted withdiethyl ether (2×50 mL) and the combined organic phases were washed withbrine, dried over sodium carbonate, and concentrated under reducedpressure. The residue was dissolved in THF (20 mL) and treated with 2Nsodium hydroxide solution (6 mL). After 2 hours, the reaction mixturewas extracted with chloroform (2×100 mL). The organic phase was driedover sodium carbonate and concentrated. Chromatography on silica gel(1:3:6 triethylamine/ethyl acetate/hexanes as eluent) afforded product(1.85 g) as a viscous oil (m/e=505).

To a stirred, cooled (0° C.) solution of previously prepared formamidine(1.37 g, 5.41 mmol.) in ethanol (50 mL) was added water (6 mL) followedby acetic acid (6 mL) and hydrazine hydrate (11 mL). The reaction vesselwas placed in the freezer (-10° C.) for 72 hours. The mixture was warmedto ambient temperature and concentrated under reduced pressure. Thecrude product was dissolved in chloroform (300 mL) and washed with water(3×50 mL). The organic phase was dried over sodium carbonate andconcentrated to a viscous oil. The oil was dissolved in diethyl etherand treated with anhydrous HCl. The hydrochloride salt (560 mg) wasisolated by filtration. Recrystallization from ethanol (2×) affordedmaterial of constant rotation. Chiral HPLC confirmed enantiomeric purityas >98% ee. m/e=336)

specific rotation @ 589 nM=-118.0 (pyridine, C=1)

specific rotation @ 365 nM=-401.0 (pyridine, C=1)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               67.64    67.65                                                H               6.76     6.70                                                 N               7.51     7.52                                                 ______________________________________                                    

EXAMPLE 47 Preparation of(±)6-methyl-1-(1-(4-methoxy-naphthalenyl)methyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole hydrochloride ##STR44##

A solution of 4-methoxy-1-naphthaldehyde (20.0 g, 0.107 mol.),N-acetylglycine (12.58 g, 0.107 mol.) and sodium acetate (8.81 g, 0.107mol) in acetic anhydride mL ) was heated to 100° C. for 2 hours. Thereaction mixture was cooled to ambient temperature and stirred for 10hours under nitrogen atmosphere. The mixture was poured onto ice (250mL) with stirring. The product was isolated by filtration, washed withwater (3×50 mL) and diethyl ether (3×50 mL) and dried under reducedpressure (3.16 g). ##STR45##

A suspension of azalactone prepared above (2.00 g, 7.5 mmol.) and5-methyl-tryptamine hydrochloride (1.18 g, 5.62 mmol.) in 1N HCl (20 mL)was heated to reflux for 48 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The brown solid was triturated with isopropylalcohol (3×50 mL) and washed with diethyl ether (3×50 mL).Recrystallization from ethanol afforded 1.42 g of desired product as apale solid. (mp 271.7° C.)

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               73.36    73.60                                                H               6.41     6.51                                                 N               7.13     7.20                                                 ______________________________________                                    

EXAMPLE 48 Preparation of(±)6-methyl-1-(1-(2-methoxy-naphthalenyl)methyl)1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole hydrochloride

To a stirred, cooled (-78° C.) solution ofmethoxymethyl-triphenylphosphonium chloride (11.05 g, 32.2 mmol.) in 150mL of anhydrous THF was added n-butyllithium (20.14 mL of 1.6M solutionin hexanes, 32.2 mmol) dropwise via syringe. After complete addition,the solution was stirred at this temperature for 15 min. A solution of2-methoxy-1-naphthaldehyde (5.0 g, 26.9 mmol.) in THF (75 mL) was addedto the solution dropwise by addition funnel. After complete addition,the solution was allowed to warm to ambient temperature and stir for 14hours. A saturated solution of ammonium chloride (100 mL) was added andthe mixture was partitioned between diethyl ether and water. The organicphase was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The crude residue was purified by plugfiltration (silica gel, eluent 40% ethyl acetate/hexanes) and afforded5.0 g of product as a mixture of enol ethers, which was used withoutfurther purification.

A solution of enol ethers prepared above (5.0 g, 23.3 mmol.) in diethylether (50 mL) was treated with water (1.0 mL) and perchloric acid (1.5mL of 60% solution). The solution was stirred at ambient temperature for72 hours. The solution was diluted with chloroform (100 mL) andneutralized with saturated sodium bicarbonate solution. The mixture wasextracted with chloroform (3×100 mL) and the combined organic phaseswere dried over sodium sulfate and concentrated. The residue waspurified by flash chromatography on silica gel (5% diethyl ether/hexanesas eluent) to afford (2-methoxy-1-naphthyl)-acetaldehyde (1.79 g) as acolorless oil.

To a stirred solution of 5-methyltryptamine hydrochloride (947 mg, 4.49mmol.) in 20 mL of ethyl alcohol was added(2-methoxy-1-naphthyl)-acetaldehyde (1.0 g, 4.99 mmol.). The solutionwas heated to reflux under nitrogen atmosphere for 40 hours. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. Recrystallization from ethyl alcohol/2-butanoneafforded product as a pale solid (705 mg). (mp. 245.3° C.).

    ______________________________________                                        Analysis:       Calculated                                                                             Found                                                ______________________________________                                        C               73.36    73.29                                                H               6.41     6.64                                                 N               7.13     7.12                                                 ______________________________________                                    

EXAMPLE 49 Preparation of(±)6-methyl-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (Z)2-butenedioate ##STR46##

To methanesulfonic acid (215 mL) was added phosphorus pentoxide (31.8 g)slowly with stirring. After the addition was complete, the mixture wasfurther stirred under nitrogen atmosphere for 2 hours until homogeneous.To this solution was added 1-naphthyl acetonitrile (50 g, 0.3 mol.) in asingle portion, followed by 2-methyl-2,4-pentanediol (76.4 mL, 0.6 mol.)dropwise at such a rate as to maintain a temperature between 25° and 30°C. (1 hour). After complete addition, the reaction mixture was stirredat ambient temperature for 10 hours and poured onto ice (500 g). Themixture was made basic with sodium hydroxide solution (50%), added atsuch a rate as to keep the temperature below 35° C. The mixture wasextracted with diethyl ether (3×250 mL) and the combined organic phaseswere dried over magnesium sulfate and concentrated under reducedpressure to afford a green solid. Recrystallization from ethyl acetateafforded product (28.29 g which was used without further purification.##STR47##

To a stirred, cooled (-78° C.) solution of previously prepared"isoxazan?" (28.3 g, 0.106 mol.) in THF (475 mL) under argon atmospherewas added t-butyllithium solution (68.4 mL, 1.7M in pentane, 0.116 mol.)dropwise via syringe over 15 minutes. After complete addition, theorange solution was stirred at -78° C. for 30 minutes. Methyl iodide(6.6 mL, 0.106 mol.) was added dropwise via syringe and the resultingsolution further stirred at -78° C. for 45 minutes. t-Butyllithium (68.4mL, 1.7M in pentane, 0.116 mol.) was added dropwise over 15 minutes andthe orange solution stirred for 2 hours. The mixture was poured intoice/water (500 mL) and was acidified to pH 2-3 with 5N HCl solution. Themixture was extracted with diethyl ether (2×100 mL) and these extractswere discarded. The aqueous phase was made basic with sodium hydroxidesolution (50%), cooling the mixture with ice when necessary. The basicaqueous phase was extracted with diethyl ether (2×200 mL) and thecombined organic extracts were dried over magnesium sulfate, filteredand concentrated to afford product as an oily solid (13.15 g), which wasused without further purification. ##STR48##

To a stirred cooled (-40° C.) solution of previous product (13.15 g,46.7 mmol.) in THF (100 mL) and ethyl alcohol (100 mL) was added 5N HClsolution until pH 7. In a separate flask, a solution of sodiumborohydride (2.52 g, 65.8 mmol.) was dissolved in water (20 mL) to which1 drop of 50% sodium hydroxide had been added. Portions of the sodiumborohydride solution and 5N HCl solution were alternately added to thereaction mixture such that the pH remained 6-8, at such a rate as tomaintain temperature between -35° and -45° C. After complete addition,the reaction mixture was warmed to ambient temperature over about 2hours. The reaction mixture was made basic with sodium hydroxidesolution and extracted with diethyl ether (3×100 mL). The combinedorganic phases were washed with brine and dried over magnesium sulfate.Filtration and removal of solvent afforded crude product (13.2 g) as aviscous oil, which was used without further purification. ##STR49##

A mixture of crude product from the previous reaction (13.2 g, 46.6mmol) and oxalic acid dihydrate (19.1 g, 152 mmol.) in water (380 mL)was heated to reflux for 12 hours. The mixture was cooled to ambienttemperature and extracted with chloroform (2×100 mL). The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated to afford aldehyde as an orange oil. Distillation(Kugelrohr) under reduced pressure afforded pure aldehyde (1.97 g) as apale oil. ##STR50##

A solution of 5-methyl tryptamine hydrochloride (1.11 g, 5.27 mmol.) and2-(1-naphthyl)-propionaldehyde (0.97 g, 5.26 mmol.) in 95% ethyl alcoholwas heated to reflux for 48 hours under nitrogen atmosphere. The mixturewas cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between aqueous potassiumcarbonate solution and chloroform. The chloroform phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to flash chromatography on silica gel (25% methyl alcoholin chloroform as eluent), affording 529 mg of the higher rf isomer and200 mg of the lower rf isomer. Each diastereomer, independently, wasdissolved in ethyl acetate and treated with excess maleic acid. Themaleate salts were isolated by filtration affording 570 mg of isomer Aand 30 mg of isomer B.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               73.66    73.64                                                H               6.18     6.13                                                 N               6.14     6.44                                                 ______________________________________                                    

isomer B data: m/e=340

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               73.66    73.41                                                H               6.18     6.04                                                 N               6.14     5.89                                                 ______________________________________                                    

EXAMPLE 50 Preparation of(±)6-(1,1-dimethylethyl)-1-(1-naphthalenyl-1-ethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

4-Chlorobutyryl chloride (300 g, 2.13 mol.) was dissolved in dry THF (3L). To this solution was added 2,6-lutidine (252 mL) followed by 5% Pd/C(30 g). This mixture was placed in a Parr hydrogenator and shaken under60 psi of hydrogen for 6 hours. The mixture was purged with nitrogen,filtered, washing the catalyst with THF (500 mL), and concentrated atroom temperature under reduced pressure. Distillation afforded4-chlorobutanal (148.3 g) as a colorless liquid.

To a stirred suspension of 4-isopropylphenylhydrazine hydrochloridemonohydrate (15.3 g, 91.95 mmol.) in chloroform (250 mL) was addedsaturated sodium carbonate solution (250 mL). The mixture was stirredfor 30 minutes until the organic phase appeared homogeneous, andextracted with chloroform (2×200 mL). The combined organic phases wereconcentrated to afford the hydrazine free base as a yellow oil. This oilwas dissolved in methanol (200 mL) and water (5 mL) and treated withsodium acetate (6.72 g, 82 mmol.) and 4-chlorobutanal (8.7 g, 82 mmol.).The mixture was placed in a sealable tube and purged with nitrogen for10 minutes. The tube was sealed and placed in an oil bath preheated to100° C. Heating was continued for 18 hours. The resulting dark solutionwas cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between chloroform/methanol (75/25by volume) and aqueous sodium carbonate solution. The organic phase wasconcentrated and the crude indole ethanamine was purified by flashchromatography on silica gel (0-25% methanol gradient in chloroform aseluent). Fractions containing product were combined and concentrated.The oil was dissolved in diethyl ether (300 mL) containing 1% methanoland treated with dry HCl gas. The hydrochloride salt was isolated byfiltration, washed with 2-propanol (50 mL) and diethyl ether (100 mL)and dried to afford 5-isopropyl-tryptamine hydrochloride (9.8 g) as apale solid, which was used without further purification.

A solution of 5-isopropyltryptamine hydrochloride (1.24 g, 5.19 mmol.)and 2-(1-naphthyl)-propionaldehyde (0.95 g, 5.16 mmol.) in 95% ethylalcohol was heated to reflux for 48 hours under nitrogen atmosphere. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between aqueous potassiumcarbonate solution and chloroform. The chloroform phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to flash chromatography on silica gel (25% methyl alcoholin chloroform as eluent), affording 500 mg of the higher rf isomer alongwith 400 mg of impure lower rf isomer. The major diastereomer wasdissolved in ethyl acetate and treated with excess maleic acid. Themaleate salt was isolated by filtration affording 400 mg of namedproduct as a pale solid.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               74.36    74.58                                                H               6.66     6.64                                                 N               5.78     5.81                                                 ______________________________________                                    

EXAMPLE 51 Preparation of(±)6-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

A solution of 1-naphthaldehyde (25.0 g, 0.16 mol.), N-acetylglycine(19.0 g, 0.162 mol.) and sodium acetate (13.1 g, 0.160 mol) in aceticanhydride (147 mL) was heated to 100° C. for 4 hours. The reactionmixture was cooled to ambient temperature poured onto ice (300 mL) withstirring. The product was isolated by filtration, washed with water(3×50 mL) and diethyl ether (3×50 mL) and dried under reduced pressure(11.82 g).

A suspension of azalactone prepared above (3.15 g, 13.3 mmol.) and5-methyl-tryptamine hydrochloride (2.0 g, 9.5 mmol.) in 1N HCl (50 mL)was heated to reflux for 24 hours under nitrogen atmosphere. Thereaction mixture was cooled to ambient temperature and the crude productisolated by filtration. The brown solid was triturated with isopropylalcohol (3×50 mL) and washed with diethyl ether (3×50 mL).Recrystallization from ethanol afforded 1.94 g of desired product as apale solid.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               76.12    76.03                                                H               6.39     6.22                                                 N               7.72     7.52                                                 ______________________________________                                    

EXAMPLE 52 Preparation of(±)8-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride ##STR51##

To a stirred suspension of 2-bromophenyl-hydrazine hydrochloride (25.8g, 115 mmol.) in chloroform (500 mL) was added saturated sodiumcarbonate solution (500 mL). The mixture was stirred for 30 minutesuntil the organic phase appeared homogenous, and extracted withchloroform (2×200 mL). The combined organic phases were concentrated toafford the hydrazine free base as a yellow oil. This oil was dissolvedin methanol (100 mL) and treated slowly with 4-chlorobutanal (preparedas described in Example 4) (12.3 g, 115 mmol.). The mixture was placedin a sealable tube and purged with nitrogen for 10 minutes. The tube wassealed and placed in an oil bath preheated to 95° C. Heating wascontinued for 18 hours. The resulting dark solution was cooled toambient temperature and concentrated under reduced pressure. The residuewas partitioned between chloroform/methanol (75/25 by volume) andaqueous sodium carbonate solution. The organic phase was concentratedand the crude indole ethanamine was purified by flash chromatography onsilica gel (0-25% methanol gradient in chloroform as eluent). Fractionscontaining product were combined and concentrated. The oil was dissolvedin diethyl ether (300 mL) containing 1% methanol and treated with dryHCl gas. The hydrochloride salt was isolated by filtration, washed with2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford7-bromo-tryptamine hydrochloride (3.6 g) as a pale solid, which was usedwithout further purification.

A suspension of azalactone (prepared as described in Example 5) (55 g,6.53 mmol.) and 7-bromo-tryptamine hydrochloride (1.50 g, 5.44 mmol.) in1N HCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The brown solid was trituratedwith isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50mL). Recrystallization from ethanol afforded 260 mg of desired productas a pale solid. (mp=231°-233° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               61.77    61.48                                                H               4.71     4.63                                                 N               6.55     6.73                                                 ______________________________________                                    

EXAMPLE 53 Preparation of(±)8-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

To a stirred suspension of 2-bromophenyl-hydrazine hydrochloride (25.8g, 115 mmol.) in chloroform (500 mL) was added saturated sodiumcarbonate solution (500 mL). The mixture was stirred for 30 minutesuntil the organic phase appeared homogenous, and extracted withchloroform (2×200 mL). The combined organic phases were concentrated toafford the hydrazine free base as a yellow oil. This oil was dissolvedin methanol (100 mL) and treated slowly with 4-chlorobutanal (preparedas described in Example 4) (12.3 g, 115 mmol.). The mixture was placedin a sealable tube and purged with nitrogen for 10 minutes. The tube wassealed and placed in an oil bath preheated to 95° C. Heating wascontinued for 18 hours. The resulting dark solution was cooled toambient temperature and concentrated under reduced pressure. The residuewas partitioned between chloroform/methanol (75/25 by volume) andaqueous sodium carbonate solution. The organic phase was concentratedand the crude indole ethanamine was purified by flash chromatography onsilica gel (0-25% methanol gradient in chloroform as eluent). Fractionscontaining product were combined and concentrated. The oil was dissolvedin diethyl ether (300 mL) containing 1% methanol and treated with dryHCl gas. The hydrochloride salt was isolated by filtration, washed with2-propanol (50 mL) and diethyl ether (100 mL) and dried to afford7-bromo-tryptamine hydrochloride (3.6 g) as a pale solid, which was usedwithout further purification.

A suspension of azalactone (prepared as described in Example 5) (55 g,6.53 mmol.) and 7-bromo-tryptamine hydrochloride (1.50 g, 5.44 mmol.) in1N HCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andthe crude product isolated by filtration. The brown solid was trituratedwith isopropyl alcohol (3×50 mL) and washed with diethyl ether (3×50mL). Recrystallization from ethanol afforded 260 mg of desired productas a pale solid. (mp=231°-233° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               61.77    61.48                                                H               4.71     4.63                                                 N               6.55     6.73                                                 ______________________________________                                    

EXAMPLE 54 Preparation of(±)8-methoxy-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (Z)-2-butenedioate

To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazinehydrochloride (14.44 g, 83 mmol.) in THF (600 mL) was added4-chlorobutanal prepared as described in Example 5 (9.0 g, 84 mmol.)followed by dropwise addition of triethylamine (8.6 g, 85 mmol.) in THF(20 mL). Upon complete addition, the cooling bath was removed and thesolution stirred for 1 hour. The reaction mixture was filtered and thefilter cake washed with THF (100 mL). The combined filtrates wereconcentrated to an orange oil, which was dissolved in methanol (150 mL)and water (5 mL). The solution was transferred to a sealable tube andpurged with nitrogen for 10 minutes. The tube was sealed and placed inan oilbath preheated to 95° C. After heating for 14 hours, the reactionmixture was cooled to ambient temperature and concentrated under reducedpressure. The residue was partitioned between saturated aqueouspotassium carbonate and 3:1 chloroform:2-propanol. The organic phase wasdried over sodium sulfate and concentrated. The residue was purified byflash chromatography on silica gel (15% methanol, 0.2% NH₄ OH, inchloroform as eluent). The fractions containing product were pooled andconcentrated under reduced pressure. The residue was dissolved inmethanol and treated with dry HCl and concentrated to afford7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which wasused without further purification.

A suspension of azalactone (prepared as described in Example 5) (1.30 g,5.5 mmol.) and 7-methoxytryptamine hydrochloride (1.08 g, 4.8 mmol.) in1N HCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (880 mg) byfiltration. (mp=226°-227° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               70.73    70.61                                                H               5.72     5.77                                                 N               6.11     6.03                                                 ______________________________________                                    

EXAMPLE 55 Preparation of(±)6-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (Z)-2-butenedioate

A suspension of azalactone (prepared as described in Example 5) (1.4 g,5.9 mmol.) and 5-bromotryptamine hydrochloride (1.77 g, 6.4 mmol.) in 1NHCl (100 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (540 mg) byfiltration. (mp=234°-235° C., dec.) m/e=390.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               61.55    61.38                                                H               4.57     4.64                                                 N               5.52     5.29                                                 ______________________________________                                    

EXAMPLE 56 Preparation of (±)7-methyl-8-bromo-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole hydrochloride

2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared asdescribed for 2-bromo-4 methylphenylhydrazine hydrochloride in Example7, except using 2-bromo-3-methylaniline as starting material. ##STR52##

6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 7,except using 2-bromo-3-methyl phenylhydrazine hydrochloride as startingmaterial.

A suspension of azalactone (prepared as described in Example 5) (1.07 g,4.51 mmol.) and 6-methyl-7-bromotryptamine hydrochloride (1.22 g, 4.21mmol.) in 1N HCl (70 mL) was heated to reflux for 65 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The solvent was removed underreduced pressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated with dryHCl. The product was isolated as the hydrochloride salt (840 mg) byfiltration. (mp=276°-279° C., dec.)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               62.53    62.79                                                H               5.02     4.96                                                 N               6.34     6.19                                                 ______________________________________                                    

EXAMPLE 57 Preparation of(±)6-cyclohexyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

4-Cyclohexyl phenylhydrazine hydrochloride (35.6 g) was prepared asdescribed for 2-bromo-4 methylphenylhydrazine hydrochloride in Example7, except using 4-cyclohexyl-aniline as starting material. ##STR53##

5-Cyclohexyltryptamine hydrochloride was prepared (1.29 g) as describedfor 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using4-cyclohexylphenylhydrazine hydrochloride as starting material.

A suspension of azalactone (prepared as described in Example 5) (1.09 g,4.59 mmol.) and 5-cyclohexyltryptamine hydrochloride (1.28 g, 4.59mmol.) in 1N HCl (70 mL) was heated to reflux for 14 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and the crude product isolated by filtration. The solid wasrecrystallized from ethanol (2×) to afford 690 mg of desired product asa pale solid hydrochloride salt. m/e=395

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               78.03    78.26                                                H               7.25     7.06                                                 N               6.50     6.48                                                 ______________________________________                                    

EXAMPLE 58 Preparation of(±)2,6-dimethyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride

To an aqueous solution (200 mL) of5-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole hydrochloride (2.00 g, 5.51 mmol.) previously prepared inExample 5, was added formic acid (4.1 mL) and formaldehyde solution (0.8mL of 37% aqueous solution). The mixture was heated to reflux for 72hours. The solution was made basic with saturated potassium carbonatesolution and extracted with chloroform (2×100 mL). The combined organicphases were dried over potassium carbonate and concentrated underreduced pressure. The crude product was purified by flash chromatographyon silica gel (chloroform as eluent). The fractions containing productwere pooled and concentrated to a viscous oil. The oil was dissolved indiethyl ether and treated with anhydrous HCl and the resultinghydrochloride salt was isolated by filtration. Drying afforded the namedproduct (1.34 g). m/e=340.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               76.48    76.58                                                H               6.68     6.63                                                 N               7.43     7.28                                                 ______________________________________                                    

EXAMPLE 59 Preparation of(±)5-fluoro-6-methyl-1-(1-naphthalenylmethyl)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (Z)-2-butenedioate

3-fluoro-4-methyl-phenylhydrazine hydrochloride (21.4 g) was prepared asdescribed for 2-bromo-4 methyl-phenylhydrazine hydrochloride in Example7, except using 3-fluoro-4-methyl aniline as starting material.##STR54##

4-Fluoro-5-methyltryptamine hydrochloride was prepared (2.20 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 7,except using 3-fluoro-4-methyl-phenylhydrazine hydrochloride (6.00 g) asstarting material.

A suspension of azalactone (prepared as described in Example 5) (2.3 g,9.6 mmol.) and 4-fluoro-5-methyltryptamine hydrochloride (2.2 g, 9.6mmol.) in 1N HCl (40 mL was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (520 mg) byfiltration.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               70.42    70.45                                                H               5.47     5.41                                                 N               6.08     6.10                                                 ______________________________________                                    

EXAMPLE 60 Preparation of(±)7,8,9,10-tetrahydro-10-(1-naphthalenylmethyl)-11H-benzo g!pyrido3,4-b!indole (Z)-2-butenedioate ##STR55##

6,7-benzotryptamine hydrochloride was prepared (2.85 g) as described for5-methyl-7-bromotryptamine hydrochloride in Example 7, except using1-naphthyl-hydrazine hydrochloride (6.00 g) as starting material.

A suspension of azalactone (prepared as described in Example 5) (2.75 g,11.6 mmol.) and 6,7-benzotryptamine hydrochloride (2.85 g, 11.6 mmol.)in 1N HCl (50 mL) was heated to reflux for 24 hours under nitrogenatmosphere. The reaction mixture was cooled to ambient temperature,neutralized with saturated aqueous potassium carbonate solution andextracted with chloroform. The solvent was removed under reducedpressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (300 mg) byfiltration. m/e=363.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               75.30    75.04                                                H               5.48     5.36                                                 N               5.85     5.76                                                 ______________________________________                                    

EXAMPLE 61 Preparation of(±)6-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido3,4b!indole (Z)-2-butenedioate ##STR56##

5-(1,1-dimethylethyl)-tryptamine hydrochloride was prepared (2.95 g) asdescribed for 5-methyl-7-bromotryptamine hydrochloride in Example 7,except using 4-(1,1-dimethylethyl)-phenyl hydrazinc hydrochloride (6.00g) as starting material.

A suspension of azalactone (prepared as described in Example 5) (1.25 g,5.26 mmol.) and 5-(1,1-dimethylethyl)-tryptamine hydrochloride (1.33 g,5.26 mmol.) in 1N HCl (50 mL) was heated to reflux for 24 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature, neutralized with saturated aqueous potassium carbonatesolution and extracted with chloroform. The solvent was removed underreduced pressure and the residue chromatographed on silica gel (ethylacetate/0.2% NH₄ OH as eluent). The fractions containing product werepooled and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate containing 1% methanol and treated withmaleic acid. The product was isolated as the maleate salt (700 mg) byfiltration. m/e=369

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               74.36    74.08                                                H               6.66     6.69                                                 N               5.78     5.69                                                 ______________________________________                                    

EXAMPLE 62 Preparation of(±)6-(1-methylethyl)-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido3,4b!indole (Z)-2-butenedioate

A suspension of azalactone (prepared as described in Example 5) (1.75 g,7.38 mmol.) and 5-isopropyltryptamine hydrochloride (prepared asdescribed in Example 4) (1.76 g, 7.37 mmol.) in 1N HCl (40 mL) washeated to reflux for 24 hours under nitrogen atmosphere. The reactionmixture was cooled to ambient temperature, neutralized with saturatedaqueous potassium carbonate solution and extracted with chloroform. Thesolvent was removed under reduced pressure and the residuechromatographed on silica gel (ethyl acetate/0.2% NH₄ OH as eluent). Thefractions containing product were pooled and concentrated under reducedpressure. The residue was dissolved in ethyl acetate containing 1%methanol and treated with maleic acid. The product was isolated as themaleate salt (671 mg) by filtration. m/e=355

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               74.02    74.08                                                H               6.43     6.21                                                 N               5.95     5.83                                                 ______________________________________                                    

EXAMPLE 63 Preparation of(±)6,9-dimethyl-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido3,4-b!indole hydrochloride

To a stirred suspension of 5-methyltryptamine hydrochloride (10.0 g,43.2 mmol.) in chloroform (300 mL) was added saturated sodium carbonatesolution (300 mL). The mixture was stirred at ambient temperature for 1hour. The layers were separated and the aqueous layer was back extractedwith chloroform (2×100 mL). The combined organic layers were dried oversodium sulfate and concentrated. The residue was dissolved in toluene(300 mL) and treated with phthalic anhydride (7.05 g, 47.6 mmol.). Thesolution was heated to reflux for 14 hours with azeotropic removal ofwater (by Dean-Stark trap). The solution was cooled to ambienttemperature and concentrated to afford crude product as a pale foam.Recrystallization from ethanol afforded product phthalimide (13.52 g) asa white solid, which was used without further purification.

To a stirred, cooled (0° C.) suspension of potassium hydride (25% oildispersion, 8.24 g, 51.3 mmol.) in dry THF (50 mL) was added a solutionof phthalimide prepared above (13.02 g, 42.8 mmol.) in THF (150 mL) over30 minutes. After complete addition, the mixture was further stirred for1 hour. Tetramethylethylenediamine (7.7 mL , 51.3 mmol.) was added,followed by methyl iodide (4.0 mL, 63.8 mmol.). After 1 hour, thereaction was quenched by addition of water (200 mL), followed byextraction with diethyl ether (2×100 mL). The combined organic phaseswere dried over magnesium sulfate and concentrated under reducedpressure to afford product as a yellow solid (14 g) which was usedwithout further purification.

A solution of phalimide prepared in the previous step (14 g, 42.8 mmol.)in methanol (85 mL) was treated with hydrazine (3.4 mL, 109 mmol.). Themixture was heated to reflux for 2 hours. The mixture was cooled toambient temperature, treated with concentrated HCl (7 mL) and methanol(25 mL), and further heated to reflux for 14 hours. After cooling toambient temperature, the mixture was partitioned between chloroform (200mL) and saturated aqueous sodium carbonate solution (200 mL). Theaqueous layer was further extracted with chloroform (2×100 mL) and theorganic phases combined, dried over sodium sulfate and concentrated. Thecrude product was purified by flash chromatography on silica gel (0-25%methanol in chloroform/0.2% NH₄ OH as eluent). The product containingfractions were pooled and concentrated under reduced pressure. Theresidue was dissolved in diethyl ether and treated with anhydrous HCl.The product 1,5-dimethyl-tryptamine hydrochloride (6.08 g) was isolatedby filtration as a tan solid and used without further purification.

A suspension of azalactone prepared as described in Example 5 (1.06 g,4.45 mmol.) and 1,5-dimethyl-tryptamine hydrochloride (1.00 g, 4.47mmol.) in 1N HCl (50 mL) was heated to reflux for 48 hours undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and the crude product isolated by filtration. The brownsolid was triturated with isopropyl alcohol (3×50 mL) and washed withdiethyl ether (3×50 mL). Recrystallization from ethanol afforded 710 mgof desired product as a pale solid. m/e=340.

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               76.48    76.78                                                H               6.68     6.58                                                 N               7.43     7.50                                                 ______________________________________                                    

EXAMPLE 64 Preparation of(-)-(S)-6-methyl-1,2,3,4-tetrahydro-1-(1-naphthalenylmethyl)-9H-pyrido3,4-b!indole hydrochloride

To a stirred solution of 6-methyl-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole (3.14 g, 16.9 mmol.) in dry xylenes (65 mL) was added(S)-N,N-dimethyl-N'-(1-tert-butoxy-3-methyl)-2-butylformamidine (3.79 g, 17.7 mmol.) followed by camphor sulfonic acid (200 mg). The resultingsolution was heated to reflux for 72 hours. The solution was cooled toambient temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (1:3:6triethylamine:ethyl acetate:hexanes as eluent). The product containingfractions were pooled and concentrated to afford the product formamidine(5.99 g) as a viscous oil which was used without further purification.

To a stirred, cooled (0° C.) suspension of potassium hydride (25% oildispersion, 829 mg, 20.2 mmol.) in THF (10 mL) was added formamidineprepared above (5.99 g, 16.8 mmol.) in THF (45 mL). To this mixture wasadded tetramethylethylenediamine (3.0 mL, 20.2 mmol.) followed bychloromethylmethyl ether (1.9 mL, 25.2 mmol.). The mixture was stirredfor an additional 1 hour and treated with water (50 mL). The mixture waspartitioned between diethyl ether and water and the layers separated.The aqueous phase was extracted with diethyl ether (2×100 mL) and theorganic phases combined, dried over potassium carbonate, andconcentrated to afford product (6.73 g) as an orange oil, which was usedwithout further purification.

To a stirred, cooled (-78° C.) solution of previously preparedformamidine (3.36 g, 8.4 mmol.) in dry THF (55 mL) was added n-BuLi(1.7M solution in hexanes, 5.4 mL, 9.18 mmol.) dropwise over 5 minutes.The solution was further stirred at -78° C. solution for 1 hour andtreated with 1-chloromethyl-naphthalene (1.62 g, 9.18 mmol.) in dry THF(10 mL). The solution was further stirred for 4 hours at -78° C. andallowed to warm to room temperature overnight. Wet THF was added (50 mL)and the solution was concentrated under reduced pressure. The residuewas dissolved in chloroform and washed with water. The organic phase wasdried over sodium carbonate and concentrated. The crude product waspurified by flash chromatography on silica gel (1:3:6triethylamine:ethyl acetate:hexanes as eluent). The product containingfractions were pooled and concentrated to afford product (3.48 g) as aviscous oil (m/e=539) which was used without further purification.

To a stirred solution of methoxymethyl indole prepared above (3.48 g ,6.45 mmol.) in THF (30 mL) was added 2N HCl (30 mL). The mixture wasstirred at ambient temperature for 24 hours, and partitioned betweendiethyl ether and water. The aqueous phase was back extracted withdiethyl ether (2×50 mL) and the combined organic phases were washed withbrine, dried over sodium carbonate, and concentrated under reducedpressure. The residue was dissolved in THF (20 mL) and treated with 2Nsodium hydroxide solution (6 mL). After 2 hours, the reaction mixturewas extracted with chloroform (2×100 mL). The organic phase was driedover sodium carbonate and concentrated to afford product (2.68 g) as aviscous oil (m/e=495).

To a stirred, cooled (0° C.) solution of previously prepared formamidine(2.68 g, 5.41 mmol.) in ethanol (100 mL) was added water (12 mL)followed by acetic acid (12 mL) and hydrazine hydrate (22 mL). Thereaction vessel was placed in the freezer (-10° C.) for 72 hours. Themixture was warmed to ambient temperature and concentrated under reducedpressure. The crude product was dissolved in chloroform (300 mL) andwashed with water (3×50 mL). The organic phase was dried over sodiumcarbonate and concentrated to a viscous oil. The oil was dissolved indiethyl ether and treated with anhydrous HCl. The hydrochloride salt(1.50 g) was isolated by filtration. Recrystallization from ethanol (2×)afforded material of constant rotation. Chiral HPLC confirmedenantiomeric purity as >95% ee. m/e=326)

specific rotation @ 589 nM=-40.21 (pyridine, C=1)

specific rotation @ 365 nM=+80.43 (pyridine, C=1)

    ______________________________________                                        Analysis        Calculated                                                                             Found                                                ______________________________________                                        C               76.12    75.96                                                H               6.39     6.56                                                 N               7.72     7.44                                                 ______________________________________                                    

EXAMPLE 65 Preparation of 6-methyl-1-(4-dimethylamino-naphthalenyl)methyl!-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole dihydrochloride-monohydrate

To a stirred, cooled (-78° C.) suspension ofmethoxymethyl-triphenylphosphonium chloride (10.32 g, 30.1 mmol.) in dryTHF (150 mL) was added n-BuLi solution 18.8 mL. 1.6M, 30.1 mmol.)dropwise by syringe. The orange suspension was stirred at -78° C. for 15min. A solution of 4-dimethylamino-1-naphthaldehyde (5.00 g, 25.1 mmol.)in THF (75 mL) was added to the ylide dropwise over 10 min. The reactionmixture was gradually warmed to ambient temperature and stirred 14 H.Saturated ammonium chloride solution (100 mL) was added and the mixtureextracted with diethyl ether (3×50 mL). The combined organic phases weredried over sodium sulfate and concentrated under reduced pressure.Chromatography on silica gel, eluting with 15% ethyl acetate/hexanesafforded product (5.43 g) as a mixture of olefin isomers which was usedwithout further purification.

A mixture of 5-methyltryptamine hydrochloride (695 mg, 3.3 mmol.) and1-methoxy-4'-dimethylamino-benzostyrene (1.00 g, 4.4 mmol.) inacetonitrile (20 mL) and 1N HCl solution (150 mL) was heated to refluxfor 96 H, with addition of 1 mL of conc HCl added at 4 H. The reactionmixture was cooled to ambient temperature, neutralized with saturatedaqueous potassium carbonate solution and extracted with chloroform. Thecombined organic phases were concentrated under reduced pressure and theresidue chromatographed on silica gel (2.5% MeOH/chloroform/0.2% NH₄ OHas eluent). The fractions containing product were pooled andconcentrated under reduced pressure. The residue was dissolved in ethylacetate and treated with anhydrous HCl. The product was isolated as thedihydrochloride salt monohydrate (1.22 g) by filtration. mp. 231.3° C.

    ______________________________________                                        analysis:       calculated                                                                             found                                                ______________________________________                                        C               65.21    65.30                                                H               6.79     6.60                                                 N               9.13     9.03                                                 ______________________________________                                    

EXAMPLE 66 7-methyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole##STR57##

A 3.0 g sample of 6-methyl-7-bromo-1H-indole-3-ethanamine hydrochloridewas dissolved in warm water. A solution of glyoxylic acid monohydrate(1.0 g) in water was added. The solution was adjusted to pH 4 usingeither potassium hydroxide or hydrochloride acid. A solid was suspendedin water and concentrated HCl was added slowly. The mixture was boiled.A solid was collected, washed with water, and vacuum dried. The solidwas partitioned between 1N NaOH and chloroform. The organic portion wasdried and concentrated to a residue which was chromatographed on silicagel using methanol in chloroform. The desired fractions were pooled andconcentrated to a solid which was dissolved in methanol, treated withgaseous HCl, and diluted with ether. A solid was collected, washed withether, and dried.

Yield: 48%

Melting Point: 321° C.

Elemental Analysis: C 47.83; H 4.89; N 9.30.

EXAMPLE 67 8-methoxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

The desired product was prepared using substantially the process ofExample 66, except that the starting material was7-methoxy-1H-indole-ethanamine.

Melting Point: 207°-209° C.

Elemental Analysis: C 60.17; H 5.56; N 8.60.

EXAMPLE 68 8-methoxy-2(N)-propyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole ##STR58##

A sample of 8-methoxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole wasprepared substantially as described in Example 66. A 0.36 g sample ofthe indole was contacted with 1 g K₂ CO₃ and the mixture was purged withnitrogen. A 40 mL sample of CH₃ CN was added to the resulting mixture. A0.12 mL sample of 1-iodopropane was added. The mixture was maintainedunder nitrogen and stirred in the dark. The resulting mixture wasextracted. The organic phase was dried, evaporated, and chromatographed.The desired fractions were evaporated, taken up into methanol:ethylacetate. The resulting mixture was added to a stirring ether solutionthrough which gaseous HCl was bubbled. The resulting solid was vacuumdried, recrystallized, and evaporated to yield the desired product.

Yield: 0.10 g

Melting Point: 282°-284° C.

Elemental Analysis: C 64.45; H 7.67; N 9.91.

EXAMPLE 69 8-methoxy-2(N)-methyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole ##STR59##

A sample of 8-methoxy-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole wasprepared substantially as described in Example 66. The indole (1 g),NaOAc (0.34 g), NaBH₃ CN (0.53 g), methanol (50 mL), and HOAc (1.0 g)were stirred. A 1.36 g (37% in 10 mL methanol) sample of CH₂ O was addedto the indole mixture.

The reaction was quenched using an acid, then made basic, and extracted.The organic was dried, evaporated, and chromatographed. The desiredfractions were evaporated and taken up into methanol/ethyl acetate. Theresulting mixture was added to ethereal HCl. The resulting solid wascollected and vacuum dried.

Yield: 0.84 g (79%)

Melting Point: 291°-294° C.

Elemental Analysis: C 62.06; H 6.97; N 11.32.

EXAMPLE 70 8-methoxy-2(N)-cyclopropylmethyl-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole ##STR60##

The desired product was prepared using appropriate reagents and theprocess substantially as described in Example 69.

Yield: 88%

Melting Point: 285°-287° C.

Elemental Analysis: C 65.76; H 7.47; N 9.47.

EXAMPLE 71 ##STR61##

The desired product can be prepared using appropriate reagents and theprocess substantially as described in Example 69.

Yield: 48%

Melting Point: 321° C.

Elemental Analysis: C 47.83; H 4.89; N 9.30.

EXAMPLE 72 7,8-dimethyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

A 2.30 g sample of 6,7-dimethyl-1H-indole-ethanamine was dissolved in amixture of water and isopropanol with heating. A 1.03 g sample ofglyoxilic acid monohydrate in 10 mL of water was added to the flask. Thesolution was allowed to cool and made basic by the addition of potassiumhydroxide. The reaction was stirred for 48 hours. The resulting solidwas isolated by filtration and washed with water. The solid wasdissolved in 50 mL of water and the solution was acidified by the slowaddition of concentrated HCl. Heating was initiated and an additional 5mL of concentrated HCl was added. The resulting solid was isolated bydecanting and dissolved in 10 mL of water. This solution was made basicby the addition of potassium hydroxide and extracted using 1:3isopropanol:CHCl₃. Separation and concentration of the organic layergave a viscous oil which was purified via chromatography. The oil wasdissolved in ethyl acetate and gaseous HCl was bubbled into the solutionto form the hydrochloride salt. The solid hydrochloride salt wasisolated by filtration and dried in a vacuum oven.

Yield: 54%

Melting Point: 330° C.

Elemental Analysis: C 65.75; H 7.29; N 11.62.

EXAMPLE 73 6-methyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

The desired 6-methyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indolewas prepared using appropriate reagents and the process substantially asdescribed in Example 72.

Yield: 57%

Melting Point: 346° C.

Elemental Analysis: C 48.04; H 4.68; N 9.30.

EXAMPLE 74 6,8-difluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

The desired 6,8-difluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole wasprepared using appropriate reagents and the process substantially asdescribed in Example 72.

Yield: 5%

Melting Point: 350° C.

Elemental Analysis: C 53.90; H 4.49; N 11.23.

EXAMPLE 75 8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

The desired 8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole wasprepared using appropriate reagents and the process substantially asdescribed in Example 72.

Yield: 4%

Melting Point: 337.8° C.

Elemental Analysis: C 46.17; H 4.26; N 9.52.

The following were prepared by the process substantially as described inExample 72.

8-fluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Yield: 48%

Melting Point: 329.5° C.

Elemental Analysis: C 58.58; H 5.43; N 12.37.

6-chloro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Yield: 63%

Melting Point: 317.9° C.

6-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Yield: 19%

Melting Point: 310.9° C.

6-fluoro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Yield: 38%

Melting Point: 316.6° C.

Yield: 54%

Melting Point: 330° C.

Elemental Analysis: C 65.75; H 7.29; N 11.62.

EXAMPLE 76 7-methyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole##STR62##

The desired product was prepared using the process substantially asdescribed in Example 1 except that the starting material was6-methyl-7-chloro-1H-indole-3-ethanamine hydrochloride.

Yield: 70%

The resulting material was boiled in ethanol. The resulting product wascollected, washed with ethanol, and vacuum dried.

Yield: 58%

Melting Point: 330°-334° C.

Elemental Analysis: C 55.88; H 5.47; N 10.93.

The following were prepared using the process substantially as describedabove in Example 76.

7-methyl-8-chloro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Melting Point: 350°-352° C.

Elemental Analysis: C 55.65; H 5.68; N 10.39.

8-chloro-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Melting Point: 335°-337° C.

Elemental Analysis: C 53.93; H 4.88; N 11.09.

7-bromo-8-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

Melting Point: 323°-325° C.

Elemental Analysis: C 47.85; H 4.84; N 9.08.

EXAMPLE 77 7-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole ##STR63##

A sample of 7-methyl-8-bromo-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indolewas reacted with hydrogen in the presence of Pd/C, ethanol, andtriethylamine. The resulting material was filtered, concentrated andextracted. The organic phase was dried, concentrated, and vacuum dried.The resulting solid was taken up into methanol and added to etherealHCl. A white solid was collected, washed with Et₂ O, and vacuum dried.

Yield: 56%

Melting Point: 310°-312° C.

Elemental Analysis: C 64.79; H 6.89; N 12.47.

EXAMPLE 78 8-methyl-1,2,3,4-tetrahydro-9H-pyrido 3,4b!-indole

The desired product was prepared using the process substantially asdescribed in Example 77.

Yield: 46%

Melting Point: 318°-320° C.

Elemental Analysis: C 64.53; H 6.94; N 12.43.

EXAMPLE 79 7-bromo-1H-indole-3-ethanamine ##STR64##

A 25.8 g sample of 2-bromophenylhydrazine hydrochloride was partitionedbetween 1N NaOH and chloroform. The organic layer was separated and theaqueous portion was extracted with chloroform. The combined organicextracts were dried (Na₂ SO₄) and concentrated to yield the freehydrazine as an oil.

The oil was stirred in 100 mL of methanol while 4-chlorobutyraldehyde(12.3 g) was added. The resulting solution was transferred to a sealabletube and purged with nitrogen. The tube was sealed and the reactionmixture was heated in an oil bath maintained at 95° C. for 14 hours. Theresulting mixture was allowed to cool and concentrated to a residuewhich was partitioned between 1N NaOH and chloroform. The combinedorganic extracts were dried and concentrated to an oil. The oil waschromatographed on silica gel using a gradient of 0-10% methanol inchloroform. Fractions containing product were concentrated to an oilwhich was taken up in a small amount of methanol and added to etherealHCl. A solid was collected, washed with diethyl ether and vacuum driedat 50° C.

Yield: 7.32 g

Yield: 23%

M.P.: 260°-262° C.

Elemental Analysis: C 43.55: H 4.41: N 10.03.

EXAMPLE 80 7-fluoro-1H-indole-3-ethanamine ##STR65##

The desired 7-fluoro-1H-indole-3-ethanamine was prepared substantiallyas described in Example 81 infra. except that 2-fluorophenylhydrazinehydrochloride (25.5 g) was used. Additionally, reverse phase HPLC wasrequired for final purification.

Yield: 4 g

Melting point: 187°-189° C.

Elemental Analysis: C 55.12; H 5.48; N 12.60.

EXAMPLE 81 7-methoxy-1H-indole-3-ethanamine ##STR66##

A 15.8 g sample of 2-methoxyphenylhydrazine hydrochloride and a 26.3 gsample of 4-phthalimidobutyraldehyde diethyl acetal were stirred inethanol. The mixture was heated at reflux for 2 hours. The reactionmixture was allowed to cool and was concentrated to a residue.

The resulting residue was dissolved in 750 mL ethanol and 15.5 ghydrazine hydrate was added. The mixture was heated at reflux for 14hours. A 70 mL sample of 5N HCl was added and the mixture was allowed tocool. The cooled mixture was concentrated to a residue. The residue waspartitioned between 1N NaOH and chloroform. The organic portion wasseparated and the aqueous portion was extracted with chloroform. Thecombined organic extracts were dried (Na₂ SO₄) and concentrated to anoil. The oil was chromatographed on silica gel using a gradient of 0-10%methanol in chloroform. Fractions containing product were concentratedto an oil which was taken up into a small amount of methanol and addedto ethereal HCl. A solid was collected, washed with diethyl ether, andvacuum dried at 50° C. to afford a white solid.

Yield: 7.5 g (37%)

melting point: 198°-200° C.

Elemental Analysis: C 57.51; H 6.75; N 12.10.

EXAMPLE 82 7-chloro-1H-indole-3-ethanamine ##STR67##

A 10.0 g sample of 2-chlorophenylhydrazine hydrochloride and 17.9 g of4-phthalimidobutyraldehyde diethyl acetal were stirred in 200 mL ethanolwith 1 mL 5N HCl. The mixture was concentrated to a residue which wasslurried in a small amount of methylene chloride. A yellow solid wascollected and vacuum dried at 40° C. The solid was stirred in 500 mLethanol. Hydrazine hydrate (14 g) was added and the mixture was heatedat reflux for 14 hours. A 60 mL sample of 5N HCl was added and themixture was heated at reflux for 1 hour. The mixture was allowed to cooland was concentrated to a residue. The residue was partitioned between1N NaOH and chloroform. The organic layer was separated and the aqueouslayer was extracted with chloroform. The combined extracts were dried(Na₂ SO₄) and concentrated to an oil. The oil was chromatographed onsilica gel using a gradient of 0-10% methanol in chloroform containing0.2% ammonium hydroxide. Fractions containing product were concentratedto an oil which was taken up in a small amount of methanol and added toethereal HCl. A solid was collected, washed with diethyl ether, andvacuum dried at 50° C.

Yield: 3.2 g (25%)

Melting Point: 227°-229° C.

Elemental Analysis: C 51.76; H 5.29; N 11.97.

EXAMPLE 83 5-methyl-7-chloro-1H-indole-3-ethanamine ##STR68##

The desired product was prepared substantially as described in Example82.

Yield: 4.3 g (34%)

Melting Point: 279°-281° C.

Elemental Analysis: C 54.05; H 5.85; N 11.33.

EXAMPLE 84 1-H-Benz(G)indole-3-ethanamine ##STR69##

1-H-Benz(G)indole-3-ethanamine was prepared using substantially theprocess described in Example 82.

Yield: 3.5 g (17%)

Melting Point: 305°-307° C.

Elemental Analysis: C 68.43; H 6.30; N 11.08.

EXAMPLE 856-methyl-7-chloro-1H-indole-3-ethanamine6-bromo-7-methyl-1H-indole-3-ethanamine##STR70##

6-methyl-7-chloro-1H-indole-3-ethanamine was prepared usingsubstantially the same process described in Example 82.

Yield: 3.0 g (24%)

Melting Point: 290° C.

Elemental Analysis: C 54.10; H 5.88; N 11.66.

6-bromo-7-methyl-1H-indole-3-ethanamine was prepared substantially asdescribed in Example 82 using appropriate starting materials.

Yield: 1.6 g (56%)

Melting Point: 251° C.

Elemental Analysis: C 45.85; H 4.97; N 9.71.

EXAMPLE 86 6-methyl-1H-indole-3-ethanamine ##STR71##

A sample of 6-methyl-7-bromo-1H-indole-3-ethanamine was contacted withPd/C H₂ in the presence of ethanol and triethylamine. The resultingmaterial was evaporated and partitioned between base/CHCl₃. The organicphase was dried, concentrated, and dried. The resulting material wastaken up into methanol and added to ethereal HCl. The resulting materialwas washed and vacuum dried.

Melting Point: 232°-236° C.

Elemental Analysis: C 62.84; H 7.24; N 13.20.

EXAMPLE 87 5-methyl-7-bromo-1H-indole-3-ethanamine

A sample of 5-methyl-7-bromo-1H-indole-3-ethanamine was prepared usingappropriate starting materials and substantially the process describedin Example 79.

Yield: 16%

A 0.6 g sample of 5-methyl-7-bromo-1H-indole-3-ethanamine hydrochloridesalt was converted to the free base and chromatographed on silica. Thedesired fractions were pooled and evaporated. The resulting material wastaken up into ethyl acetate, filtered, diluted with ether, and maleicacid in methanol. The product was crystallized using ether, filtered,and dried.

Yield: 67%

Melting Point: 185°-187° C.

Elemental Analysis: C 49.09; H 4.85; N 7.71.

EXAMPLE 88 6,7-dimethyl-1H-indole-3-ethanamine

A sample of 6,7-dimethyl-1H-indole-3-ethanamine was prepared usingappropriate starting materials and substantially the process describedin Example 79. The 6,7-dimethyl-1H-indole-3-ethanamine was purified bytreating with K₂ CO₃ and extracting with 3:1 CHCl₃ /isopropanol. Theorganic phase was dried, evaporated, and chromatographed. The desiredfractions were pooled, evaporated, and mixed with ethyl acetate. Theresulting material was diluted with ether and maleic acid in methanol.The solid was triturated in ether and dried.

Melting Point: 171°-173° C.

Elemental Analysis: C 63.20; H 6.75; N 8.98.

EXAMPLE 89 6-methyl-7-bromo-1H-indole-3-ethanamine

A sample of 6-methyl-7-bromo-1H-indole-3-ethanamine was prepared usingappropriate starting materials and substantially the process describedin Example 79.

Yield: 8.6%

The 6-methyl-7-bromo-1H-indole-3-ethanamine was dissolved in boilingethanol and slowly cooled to room temperature. The solvent was reduced,the resulting material was filtered, and washed with ether. Theresulting material was again filtered and washed with ether to affordthe desired compound.

Melting Point: 288°-290° C.

Elemental Analysis: C 45.54; H 4.80; N 9.47.

For Examples 90 through 110, where applicable, diethylether wasdistilled from sodium benzophenone ketyl prior to use. All reactionswere performed under a positive pressure of argon. ¹ H-NMR and ¹³ C-NMRdata were recorded on a Bruker AC-200P (200 MHz). IR spectra wereobtained on Nicolet 510 P-FT (film and KBr). Melting points weredetermined on a Buchi apparatus and are not corrected. Analytical TLCwas performed on Merck TLC glass plates precoated with F₂₅₄ silica gel60 (UV, 254 nm and Iodine). Chromatographic separations were performedby using 230-400 mesh silica gel (Merck). N-BOC-aziridines (2a-d) wereprepared from the corresponding alkenes following standard procedures.

Preparation 2 Indole starting materials

The indole starting materials (1a, 1b, and 1c) infra. were purchased(1a), prepared according to Bartoli's procedure (1b) Bartoli, G. et al.Tetrahedron Lett., 1989, 30, 2129! or (1c) synthesized from2-iodo-4,6-dimethylaniline (5"'). The process is illustrated by thefollowing Scheme: ##STR72##

The 2-Iodo-4,6-dimethylaniline (5"') synthesis can be completed asfollows: To a suspension of 5"' (24 mmol.), CuI (0.05 equiv.) and(PPh₃)₂ PdCl₂ (0.05 equiv.) in 30 ml of dry triethylamine under Aratmosphere was added trimethylsilylacetylene (1.1 equiv.) and theresulting mixture was stirred for 3 hours. Then, the solvent waseliminated under vacuum and the residue purified by flash chromatographyusing hexane/ethyl acetate (3:1) as eluent to yield 6" in quantitativeyield. A slurry of 6"' (23 mmol.) and CuI (2 equiv.) in 50 ml of drydimethylformamide was heated for 2.5 h. under Ar atmosphere at 100° C.After cooling down to room temperature the reaction mixture was filteredoff and the solid washed twice with ether (20 ml.). The organic phasewas washed with water (3×50 ml.), dried over Na₂ SO₄ and the solventevaporated to dryness. The crude product was purified by flashchromatography using hexane/ethyl acetate (3:1) as eluent to afford 1c(1.5 g., 45%).

The process for preparing compounds of Examples 90 through 107 isillustrated by the following Scheme: ##STR73##

EXAMPLE 90 Trans-3-(2-amino-cyclopentyl)-5-methylindole, hydrochloride

To a suspension of the corresponding indole 1a (5 mmol.) in 10 ml ofanhydrous ether under Ar atmosphere was added a 3M solution ofmethylmagnesium bromide (1.5 equiv.). The resulting mixture was stirredfor 45 min. at room temperature. Then, this mixture was cannulated to aslurry of Copper (I) bromide-dimethylsulfide complex (0.2 equiv.) in 5ml. of dry ether under Ar atmosphere at -30° C. The reaction mixture wasstirred for 30 min. at the same temperature. After this time the mixturewas cooled down to -78° C. and the corresponding aziridine 2a (1.5equiv.) dissolved in 10 ml. of dry ether was added. The whole mixturewas allowed to reach room temperature and stirring was kept overnight.The reaction was quenched with 10 ml. of a saturated solution ofammonium chloride. The layers were separated and the aqueous phase wasextracted with ether/ethyl acetate (1:1) (2×10 ml.). The combinedorganic extracts were dried over anhydrous sodium sulfate, the solventwas eliminated under vacuum and the residue was purified by flashchromatography using hexane/ethyl acetate (3:1). The corresponding N-BOCprotected tryptamine was dissolved in dichloromethane/ether. Thesolution was saturated with dry hydrogen chloride and stirred overnightat room temperature. Finally, the solvent was evaporated and the crudetitle tryptamines purified by washing with dichoromethane/ether/methanolmixture (2:3:1). The product was identified as the title compound (3a).

Yield: 85%. Mp: >200° C. ¹ H NMR (CD₃ OD), δ: 7.35 (s, 1H), 7.23-7.12(m, 2H), 6.91 (d, J=7.5 Hz, 1H), 3.73 (m, 1H), 3.27 (m, 1H), 2.38-2.10(m, 5H), 2.05-1.70 (m, 4H). ¹³ C NMR (CD₃ OD), δ: 136.98, 128.93,127.84, 124.27, 123.13, 119.01, 114.19, 112.37, 58.56, 43.93, 33.10,31.30, 23.07, 21.73. IR (KBr): 3304, 2963, 1593, 1510, 1481, 800 cm⁻¹.MS (EI): 214 (M⁺ -HCl, 28), 197 (70), 170 (14), 144 (42), 126 (49), 105(33), 84 (100).

EXAMPLE 91 Trans-3-(2-amino-cyclopentyl)-7-chloroindole, hydrochloride

The title compound (3b) was prepared using substantially the sameprocedure as described by Example 90; however, the indole startingmaterial was a compound of Formula 1b.

Yield: 37%. Mp: >200° C. ¹ H NMR (CD₃ OD), δ: 7,56 (d, J=7.7 Hz, 1H),7.31 (s, 1H), 7.12 (d J=7.3 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 3.77 (q,J=7.9 Hz, 1H), 3.40-3.25 (m, 1H), 2.40-2.15 (m, 2H), 2.05-1.70 (m, 4H).¹³ C NMR (CD₃ OD), δ: 135.48, 129.53, 124.28, 122.13, 120.79, 118.40,118.02, 116.18, 58.55, 43.79, 33.32, 31.36, 23.11. IR (KBr): 3422, 3298,3040, 2972, 2909, 1495 cm⁻¹. MS (EI): 235 (M⁺ -Cl, 100), 218 (28), 165(7).

EXAMPLE 92 Trans-3-(2-amino-cyclohexyl)-5-methylindole, hydrochloride

The title compound (3d) was prepared using substantially the sameprocedure as described by Example 90.

Yield: 80%. Mp: >200° C. ¹ H NMR (CD₃ OD), δ: 7,44(s, 1H), 7.27 (d,J=8.3 Hz, 1H), 7.18 (s, 1H), 6.95 (dd, J=8.3 and 1.2 Hz, 1H), 3.55-3.40(m, 1H), 2.86 (dt, J=4.3 and 11.3 Hz, 1H), 2.42 (s, 3H), 2.25-2.12 (m,1H), 2.10-1.79 (m, 4H), 1.75-1.40 (m, 3H). ¹³ C NMR (CD₃ OD), δ: 136.97,129.12, 127.74, 124.42, 123.73, 119.09, 114.77, 112.48, 56.22, 41.61,34.75, 32.42, 26.93, 25.79, 21.73. IR (KBr): 3400, 3283, 3021, 2936,2861, 1491 cm⁻¹. MS (EI): 229 (M⁺ -Cl, 100).

EXAMPLE 94 Trans-3-(2-amino-cyclohexyl)-7-chloroindole, hydrochloride(3e)

The title compound (3e) was prepared using substantially the sameprocedure as described by Example 90.

Yield: 43%. Mp: >200° C. ¹ H NMR (CD₃ OD), δ: 7,63 (d, J=7.8 Hz, 1H),7.35 (s, 1H), 7.14 (d, J=7.4 Hz, 1H), 7.02 (t, J=7.7 Hz, 1H), 3.60-3.40(s, 1H), 3.08-2.91 (m, 1H), 2.30-2.10 (m, 1H), 2.05-1.80 (m, 4H),1.75-1.45 (m, 3H). ¹³ C NMR (CD₃ OD), δ: 135.43, 129.41 125.00, 122.15,120.87, 118.53, 118.09, 116.70, 56.12, 41.43, 34.74, 32.37, 26.80,25.68. IR (KBr): 2938, 2859, 1429, 1341, 779, 735 cm⁻¹. MS (EI): 249 (M⁺-Cl, 100).

EXAMPLE 94 Trans-3-(2-amino-cyclohexyl)-5,7-dimethylindole,hydrochloride Trans-3-(2-amino-cyclopentyl)-5,7-dimethylindole,hydrochloride

The title compound (3f) was prepared using substantially the procedureof Example 90; however, the indole was 1c and the aziridine was 2b.

Yield: 45%. Mp: >200° C. ¹ H NMR (CD₃ OD), δ: 7,27 (s, 1H), 7.19 (s,1H), 6.77 (s, 1H), 3.42 (dt, J=11.0 and 4.2 Hz, 1H), 2.85 (dt, J=11.4and 4.2 Hz, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.30-2.10 (m, 1H),2.08-1.83 (m, 4H), 1.70-1.40 (m, 3H). ¹³ C NMR (CD₃ OD), δ: 136.39,129.37, 127.39, 125.01, 123.56, 121.94, 116.78, 115.16, 56.28, 41.70,34.71, 32.40, 26.93, 25.80, 21.72, 16.93. IR (KBr): 3420, 3279, 3013,2934, 2861, 1505 cm⁻¹. MS (EI): 242 (M⁺ -HCl, 62), 225 (25), 199 (23),184 (20), 171 (38), 158 (100), 145 (18), 128 (12), 115 (12), 97 (12).

Substantially the same procedure was used to prepareTrans-3-(2-amine-cyclopentyl)-5,7-dimethylindole, hydrochloride (3c);however, the aziridine was 2a.

Yield: 63%. ¹ H NMR (DMSO-d₆), δ: 10.8 (s, 1H), 8.12 (broad s, 3H),7.30-7.20 (m, 2H), 6.70 (s, 1H), 3.70-3.55 (m, 1H), 3.55-3.20 (m, 1H),2.38 (s, 3H), 2.36 (s, 3H), 2.30-2.10 (m, 2H), 2.00-1.60 (m, 4H).

EXAMPLE 95 Trans-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride

A suspension of tryptamine hydrochloride (3a) (1.3 mmol.) in 10 ml. ofdistilled water was dissolved by heating. To this solution glyoxylicacid (1.43 mmol.) in 1 ml. of water was added. Subsequently, a solutionof KOH (1.3 mmol.) in 1 ml. of distilled water was slowly added to reachpH=4. The resulting solution was stirred at room temperature for 1 h.After this time, commercially available hydrochloric acid (0.5 ml.) wasadded dropwise and the resulting mixture was refluxed for 30 min.Another portion of hydrochloric acid (0.5 ml.) was added and thereaction further refluxed for 15 min. Finally, the reaction mixture wascooled down to room temperature and filtered off. The titletetrahydro-b-carboline (4a) was subsequently washed with water andethanol.

Yield: 81%. Mp: >200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H),9.92 (broads, 1H), 9.68 (broad s, 1H), 7.38 (s, 1H), 7.23 (d, J=8.3 Hz, 1H), 6.88(d, J=7.8 Hz, 1H), 4.50-4.22 (m, 2H), 3.18-2.95 (m, 2H), 2.80-2.65 (m,1H) 2.34 (s, 3H), 2.30-2.15 (m, 1H), 1.98-1.80 (m, 2H), 1.80-1.20 (4H).¹³ C NMR (DMSO-d₆), δ: 134.75 127.31, 126.49, 125.64, 122.65, 119.11,111.14, 108.82, 58.99, 37.18, 29.42, 28.84, 24.94, 24.43, 21.28. IR(KBr): 3391, 3266, 2936, 2861, 2801, 2762 cm⁻¹. MS (EI): 241 (M⁺ -Cl,100).

EXAMPLE 96 Trans-8-chloro-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride (4b)

A suspension of tryptamine hydrochloride (3b) (1.3 mmol.) in 10 ml. ofdistilled water was dissolved by heating. To this solution glioxylicacid (1.43 mmol.) in 1 ml. of water was added. Subsequently, a solutionof KOH (1.3 mmol.) in 1 ml. of distilled water was slowly added to reachpH=4. The resulting solution was stirred at room temperature for 1 h.After this time, commercially available hydrochloric acid (0.5 ml.) wasadded dropwise and the resulting mixture was refluxed for 30 min.Another portion of hydrochloric acid (0.5 ml.) was added and thereaction further refluxed for 15 min. Finally, the reaction mixture wascooled down to room temperature and filtered off. The titletetrahydro-b-carboline (4b) was subsequently washed with water andethanol.

Yield: 45%. Mp: >200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.05(broad s, !H), 9.87 (broad s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.16 (d,J=7.6 Hz, 1H), 6.98 (t, J=7.9 Hz, 1H), 4.60-4.20 (m, 2H), 3.18-2.95 (m,2H), 2.90-2.70 (m, 1H), 2.25-2.18 (m, 1H), 1.98-1.75 (m, 2H), 1.65-1.20(4H). ¹³ C NMR (DMSO-d₆), δ: 133.17 128.18, 127.23, 120.65, 120.03,118.55, 115.78, 110.73, 58.74, 36.93, 29.16, 28.77, 24.88, 24.36. IR(KBr): 3422, 3231, 2936, 2861, 2760, 1429 cm⁻¹. MS (EI): 261 (M⁺ -Cl,30), 241 (100).

EXAMPLE 97Trans-5-(3,4-dimethoxybenzyl)-9-methyl-1,2,3,4,4a,5,6,10c-octahydrocyclopentaa!pyrido 3,4-b!indole, hydrochloride (4c)

A suspension of the corresponding tryptamine hydrochloride (3a) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 88%. Mp: 187°-191° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.38(broad s, 1H), 9.25 (broad s, 1H), 7.50-7.15 (m, 3H), 7.15-6.80 (m, 3H),5.0-4.70 (broad s, 1H), 3.75 (s, 6H), 3.40-2.80 (m), 2.49 (s, 3H),2.20-1.70 (m, 4H), 1.55-1.30 (broad s, 1H). ¹³ C NMR (DMSO-d₆), δ:148.73 147.90, 134.45, 130.24, 128.17, 127.64, 125.44, 123.03, 121.78,118.43, 113.69, 111.95, 111.27, 110.64, 62.01, 57.50, 55.51, 37.49,25.52, 25.14, 21.30, 20.73. IR (KBr): 3438, 3237, 2942, 1518, 1264, 1248cm⁻¹. MS (EI): 377 (M⁺ -Cl, 100).

EXAMPLE 98Trans-7-chloro-5-(3,4-dimethoxybenzyl)-1,2,3,4,4a,5,6,10c-octahydrocyclopentaa!pyrido 3,4-b!indole, hydrochloride (4d)

A suspension of the corresponding tryptamine hydrochloride (3b) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 52%. Mp: >230° C. dec. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.40(broad s, 1H), 9.30 (broad s, 1H), 7.60-7.42 (m, 1H), 7.38-6.90 (m, 5H),4.90-4.75 (broad s, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.40-3.00 (m),2.15-1.80 (m, 4H), 1.60-1.35 (broad s, 1H). ¹³ C NMR (DMSO-d₆), δ:148.70, 147.91, 132.95, 131.78, 128.25, 127.02, 121.75, 121.11, 120.41,117.96, 116.05, 113.54, 112.72, 111.99, 61.74, 57.45, 55.50, 37.27,25.24, 25.07, 20.77. IR (KBr): 3588, 3438, 1518, 1290 cm⁻¹. MS (EI): 398(M⁺ +2-HCl, 40), 396 (M⁺ -HCl, 100).

EXAMPLE 99Trans-5-(3,4-dimethoxybenzyl)-7,9-dimethyl-1,2,3,4,4a,5,6,10c-octahydrocyclopentaa!pyrido 3,4-b!indole, hydrochloride (4e)

A suspension of the corresponding tryptamine hydrochloride (3c ) (1mmol) and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2mmol) in 1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphereduring 72 h. After this time the reaction mixture was allowed to reachroom temperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 87%. Mp: >200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.20(broad s, 1H), 9.20 (broad s, 1H), 7.29 (s, 1H), 7.20-6.95 (m, 3H), 6.75(s, 1H), 4.90-4.70 (broad s, 1H), 3.78 (s, 6H), 3.30-2.90 (m), 2.48 (s,3H), 2.34 (s, 3H), 2.10-1.70 (m, 4H), 1.60-1.30 (broad s, 1H). ¹³ C NMR(DMSO-d₆), δ: 148.73 147.90, 134.01, 129.98, 128.31, 127.84, 125.10,123.82, 121.75, 120.42, 116.03, 113.58, 111.99, 111.21, 61.94, 57.62,55.52, 37.60, 25.57, 25.17, 21.23, 20.75, 17.07. IR (KBr): 3447, 2910,1520 cm⁻¹. MS (EI): 391 (M⁺ -Cl,100), 239 (35).

EXAMPLE 100Trans-6-(3,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride (4f)

A suspension of the corresponding tryptamine hydrochloride (3d) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 85%. Mp: 197°-200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 8.90(broad s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.16 (s, 1H),7.05-6.90 (m, 3H), 4.95-4.80 (broad s, 1H), 3.73 (s, 6H), 3.66-3.59 (m,1H), 3.25-2.80 (m, 4H), 2.35 (s, 3H), 2.20-2.10 (m, 1H), 1.95-1.20 (m,6H). ¹³ C NMR (DMSO-d₆), δ: 148.67 147.91, 134.92, 134.76, 129.72,127.85, 127.45, 125.43, 122.91, 121.85, 119.43, 113.59, 111.90, 111.30,109.45, 59.98, 55.47, 55.40, 37.08, 36.65, 29.48, 28.24, 24.94, 24.41,21.32. IR (KBr): 3439, 2936, 1516, 1464, 1453, 1265 cm⁻¹. MS (EI): 391(M⁺ -Cl, 100).

EXAMPLE 101Trans-8-chloro-6-(3,4-dimethoxybenzyl)-2,3,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride (4g)

A suspension of the corresponding tryptamine hydrochloride (3e) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 47%. Mp: >250° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 9.75(broad s, 1H), 8.90 (broad s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.20 (d,J=7.8 Hz 1H), 7.15-7.00 (m, 4H), 4.90-4.80 (broad s, 1H), 3.74 (s, 6H),3.70-3.60 (m, 1H), 3.25-2.85 (m, 4H), 2.20-2.15 (m, 1H), 1.95-1.25 (m,6H). ¹³ C NMR (DMSO-d₆), δ: 148.72, 148.00, 133.46, 131.35, 128.00,127.08, 121.86, 121.13, 120.28, 119.01, 115.99, 113.41, 111.98, 111.66,59.62, 55.53, 55.42, 54.98, 37.24, 36.49, 29.23, 28.25, 24.88, 24.34. IR(KBr): 3428, 2938, 1518, 1250 cm⁻¹. MS (EI): 410 (M⁺ -HCl, 100).

EXAMPLE 102Trans-6-(3,4-dimethoxybenzyl)-8,10-dimethyl-2,3,44a,5,6,7,11c-octahydro-1H-indolo2,3-!quinoline, hydrochloride (4h)

A suspension of the corresponding tryptamine hydrochloride (3f) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 78%. Mp: 198°-202° C. ¹ H NMR (DMSO-d₆), δ: 10.88 (s, 1H), 9.81(broad s, 1H), 8.78 (broad s, 1H), 7.24 (s, 1H), 7.20 (s, 1H), 7.10-6.90(m, 2H), 6.73 (s, 1H), 4.90-4.75 (broad s, 1H), 3.74 (s, 6H), 3.25-3.10(m, 2H), 3.10-2.80 (m, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 2.20-2.10 (m,1H), 2.00-1.80 (m, 3H), 1.60-1.10 (m, 3H). ¹³ C NMR (DMSO-d₆), δ: 148.65147.87, 134.44, 129.55, 128.17, 127.59, 125.13, 123.68, 121.90, 120.36,117.05, 113.64, 111.89, 110.04, 59.89, 55.78, 55.41, 37.17, 36.56,29.47, 28.21, 24.94, 24.43, 21.26, 17.09. IR (KBr): 3450, 2936, 1516,1493, 1264, 1240 cm⁻¹. MS (EI): 405 (M⁺ -Cl,100).

EXAMPLE 103Trans-7-(3,4-dimethoxybenzyl)-11-methyl-1,2,3,4,5,5a,6,7,8,12a-decahydrocycloheptaa!pyrido 3,4-b!indole, hydrochloride

A suspension of the corresponding tryptamine hydrochloride (3g) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 35%. Mp: 187°-190° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 9.66(broad s, 1H), 7.29-7.25 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 6.81 (d, J=8.2Hz, 1H), 6.65-6.56 (m, 2H) 4.80-4.70 (broad s, 1H), 3.66 (s, 3H), 3.43(s, 3H), 3.00-2.90 (m, 1H), 2.90-2.70 (m, 1H), 2.35 (s, 3H), 2.35-2.20(m, 1H), 1.80-1.30 (m, 8H), 0.85-0.65 (m, 1H). ¹³ C NMR (DMSO-d₆), δ:148.56 147.96, 135.12, 128.81, 128.05, 127.27, 125.32, 123.09, 121.73,118.97, 113.32, 111.85, 111.31, 110.51, 55.60, 55.08, 54.97, 51.48,36.97, 36.24, 32.74, 31.88, 26.37, 24.88, 24.14, 21.30. IR (KBr): 3414,3343, 2932, 2859, 1516, 1265 cm⁻¹. MS (EI): 405 (M⁺ -Cl, 100), 335 (20).

EXAMPLE 104Trans-9-methyl-5-(1-naphthylmethyl)-1,2,3,4a,5,6,10c-octahydrocyclopentaa!pyrido 3,4-b!indole, hydrochloride (4j)

A suspension of the corresponding tryptamine hydrochloride (3a) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 78%. Mp: >200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.45(broad s, 1H), 9.03 (broad s, 1H), 8.46 (d, J=7.9 Hz, 1H), 8.12-7.90 (m,3H), 7.70-7.40 (m, 3H), 7.40-7.25 (m, 2H), 6.96 (d, J=8.0 Hz, 1H),5.15-4.90 (broad s, 1H), 4.45-4.30 (m, 1H), 3.65-3.50 (m), 3.15-2.95 (m,1H), 2.38 (s, 3H), 2.00-1.70 (m, 4H), 1.60-1.35 (broad s, 1H). ¹³ C NMR(DMSO-d₆), δ: 134.59,133.86, 131.63, 131.32, 129.92, 129.18, 128.86,128.07, 127.74, 126.38, 125.96, 125.83, 125.48, 124.08, 123.20, 118.52,111.31, 110.97, 61.78, 55.76, 37.40, 35.13, 25.49, 25.12, 21.32, 20.67.IR (KBr): 3445, 3231, 2949, 2878, 2780, 793 cm⁻¹. MS (EI): 367 (M⁺ -Cl,100).

EXAMPLE 105Trans-10-methyl-6-(1-naphthylmethyl)-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride (4k)

A suspension of the corresponding tryptamine hydrochloride (3d) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 80%. Mp: >200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 8.40 (d,J=7.8 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.92 (d, J=8,2 Hz, 1H), 7.74 (d,J=6.8 Hz, 1H), 7.70-7.40 (m, 4H), 7.35 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.2Hz, 1H), 5.15-4.90 (broad s, 1H), 4.50-4.30 (m, 1H), 3.50-3.10 (m, 2H),3.10-2.82 (m, 2H), 2.38 (s, 3H), 2.10-1.20 (m, 7H). ¹³ C NMR (DMSO-d₆),δ: 135.05,134.90, 133.85, 131.79, 131.28, 129.36, 128.93, 128.07,127.56, 126.33, 125.94, 125.83, 125.41, 124.02, 123.10, 119.54, 111.27,109.61, 59.72, 53.97, 36.73, 35.27, 29.47, 28.37, 24.92, 24.36, 21.34.IR (KBr): 3447, 3235, 2936, 2857, 1450, 790 cm⁻¹. MS (EI): 381 (M⁺ -Cl,100).

EXAMPLE 106Trans-8,10-dimethyl-6-(1-naphthylmethyl)-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride (4l)

A suspension of the corresponding tryptamine hydrochloride (3f) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Yield: 77%. Mp: >200° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.11(broad s, 1H), 8.52 (d, J=8.2 Hz, 1H), 8.35 (broad s, 1H), 8.02 (d,J=7.3 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.82 (d, J=6.9 Hz, 1H), 7.71-7.46(m, 3H), 7.29 (s, 1H), 6.78 (s, 1H), 5.10-4.90 (broad s, 1H), 4.70-4.50(m, 1H), 3.40-3.20 (m, 2H), 3.10-2.80 (m, 2H), 2.51 (s, 3H), 2.34 (s,3H), 2.05-1.90 (m, 1H), 1.80-1.70 (m, 2H), 1.60-1.20 (m, 4H). ¹³ C NMR(DMSO-d₆), δ: 134.57,133.87, 131.95, 131.42, 129.29, 129.11, 128.81,128.04, 127.71, 126.21, 125.91, 125.83, 125.14, 124.46, 123.91, 120.46,117.14, 110.25, 59.65, 54.03, 36.66, 35.25, 29.47, 28.32, 24.94, 24.35,21.26, 17.30. IR (KBr): 3449, 2934, 2859, 2791, 1449, 779 cm⁻¹. MS (EI):395 (M⁺ -Cl, 100).

EXAMPLE 107 Trans-spiro-6,6-2-(3,4-dimethoxy)-1,2,3,4-tetrahydronaphthyl!-10-methyl-2,3,4,4a,5,6,7,11a-octahydro-1H-indolo2,3-c!quinidine, hydrochloride (4m)

A suspension of the corresponding tryptamine hydrochloride (3a) (1 mmol)and the correponding 4-alkylidene-2-methyloxazolin-5-one (1.2 mmol) in1N hydrochloric acid (3 ml.) was refluxed under Ar atmosphere during 72h. After this time the reaction mixture was allowed to reach roomtemperature and filtered off. The crude solid was purified by flashchromatography using dichloromethane/methanol (9:1) as eluent.

Epimeric mixture. Yield: 89%. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 10.12(broad s, 1H), 8.72 (broad s, 1H), 7.42 (s, 1H), 7.21 (s, 1H), 6.90-6.60(s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.30-2.80 (m, 5H), 2.35 (s, 3H),2.00-1.20 (m, 6H). ¹³ C NMR (DMSO-d₆), δ: 147.44, 134.84, 134.32,133.98, 127.42, 126.53, 126.35, 125.25, 125.13, 123.60, 123.25, 122.98,119.56, 119.43, 112.05, 111.48, 111.27, 108.78, 108.60, 57.83, 57.50,56.07, 55.56, 36.40, 31.91, 30.74, 29.39, 29.21, 28.73, 28.41, 24.92,24.38, 23.83, 21.30. IR (KBr): 3440, 2950, 1518, 1200, 1110, cm⁻¹. MS(EI): 417 (M⁺ -Cl, 100).

EXAMPLE 108Trans-1-(3,4-dimethoxybenzyl)-3,4,6-trimethyl-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole,hydrochloride (4n)

Trans-3-(2-amine-1,2-dimethylethyl)-5-methylindole, hydrochloride (3h)was prepared using substantially the procedure of Example 90; however,the aziridine was 2c.

Yield: 71%. ¹ H NMR (CD₃ OD), δ: 7,45 (s, 1H), 7.32 (d, J=8.3 Hz, 1H),7.19 (s, 1H), 7.00 (dd, J=8.4 and 1.5 Hz, 1H), 3.66 (t, J=6.9 Hz, 1H),3.28 (t, J=7.3 Hz, 1H), 2.47(s, 3H), 1.48 (d, J=7.2 Hz, 3H), 1.38 (d,J=6.6 Hz, 3H). ¹³ C NMR (CD₃ OD), δ: 136.89, 129.19, 127.68, 124.46,123.69, 119.09, 115.41, 112.44, 53.51, 36.62, 21.71, 17.06, 16.49.

A suspension of the corresponding tryptamine hydrochloride (3h) (1 mmol)and 6,7-dimethoxytetralin-2-one (1.2 mmol) in 1N hydrochloric acid (3ml.) was refluxed under Ar atmosphere during 72 h. After this time thereaction mixture was allowed to reach room temperature and filtered off.The crude solid was purified by flash chromatography usingdichloromethane/methanol (9:1) as eluent.

Yield: 32%. Mp: 195°-199° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 9.40(broad s, 1H), 8.90 (broad s, 1H), 7.40 (s, 1H), 7.30 (d, J=8.2 Hz, 1H),7.08 (s, 1H), 6.96-6.90 (m, 3H), 4.90-4.80 (broad s, 1H), 3.73 (s, 3H),3.72 (s, 3H), 3.70-3.60 (m, 2H), 3.20-3.00 (m, 3H), 2.37 (s, 3H), 1.46(broad s, 3H), 1.40 (broad s, 3H). ¹³ C NMR (DMSO-d₆), δ: 148.66 147.93,135.00, 129.21, 127.40, 125.40, 122.97, 121.82, 119.07, 113.56, 111.95,111.24, 110.34, 57.32, 55.43, 55.33, 54.60, 36.46, 32.56, 21.24, 17.06,15.92. IR (KBr): 3438, 2936, 1518, 1464, 1265, 1242, 1040 cm⁻¹. MS (EI):365 (M⁺ -Cl, 100).

EXAMPLE 109 Cis-3-(2-amine-cyclohexyl)-5-methylindole, hydrochlorideCis-6-(3,4-dimethoxybenzyl)-10-methyl-2,3,4,4a,5,6,7,11c-octahydro-1H-indolo2,3-c!quinoline, hydrochloride (4o)

The title compound (3i) was prepared following the procedure describedby Scmuszkovicz, J. et al. Tetrahedron, 1991, 47, 8653 starting from5-methylindole (1a).

Mp: 86°-90° C. ¹ H NMR (CD₃ OD), δ: 7,38 (s, 1H), 7.26 (d, J=8.3 Hz,1H), 7.11 (s, 1H), 6.96 (d, J=8.2, 1H), 3.90-3.70 (m, 1H), 3.55-3.38 (m,1H), 2.42 (s, 3H), 2.40-2.35 (m, 1H), 2.10-1.79 (m, 4H), 1.75-1.50 (m,3H). ¹³ C NMR (CD₃ OD), δ: 136.75, 129.27, 127.88, 124.63, 123.51,118.71, 114.49, 112.34, 52.60, 36.79, 29.52, 26.44, 25.85, 21.68, 21.00.IR (KBr): 3401, 3017, 2932, 2863, 1561, 1489 cm⁻¹. MS (EI): 229 (M⁺ -Cl,100).

The process for preparing the final product (4o) is illustrated by thefollowing Scheme: ##STR74##

Mp: 167°-171° C. ¹ H NMR (DMSO-d₆), δ: >11.0 (s, 1H), 8.87 (broad s,2H), 7.29-7.20 (m, 3H), 7.12-6.85 (m, 3H), 4.95-4.80 (broad s, 1H), 3.76(s, 3H), 3.75 (s, 3H), 3.70-3.60 (m), 3.25-3.00 (m, 1H), 2.36 (s, 3H),2.40-2.00 (m), 1.95-1.20 (m, 6H). ¹³ C NMR (DMSO-d₆), δ: 148.67 147.87,134.80, 128.71, 128.43, 127.63, 125.45, 123.32, 121.75, 117.82, 113.59,111.91, 111.30, 111.34, 56.99, 55.46, 55.12, 36.12, 36.65, 28.42, 27.49,24.94, 24.39, 21.23, 19.17. IR (KBr): 3439, 2934, 1516, 1263 cm⁻¹. MS(EI): 390 (M⁺ -ClH, 100).

As noted above, the compounds of the present invention are useful inblocking the effect of serotonin or other agonists at 5-HT_(2A),5-HT_(2B) and/or 5-HT_(1c) receptors. Thus, the present invention alsoprovides a method for blocking 5-HT_(2A), 5-HT_(2B) or 5-HT_(1c)receptors in mammals comprising administering to a mammal requiringblocking of a 5-HT_(2A), 5-HT_(2B), or 5-HT_(1c) receptor, respectively,a receptor blocking dose of a compound of the invention.

One particularly useful embodiment of this invention is that it providesselective ligands for the 5-HT_(2B) receptor. Compounds with a highaffinity for the 5-HT_(2B) receptor generally are cross-reactive withthe 5-HT_(2C) receptor as well. Now 5-HT_(2B) receptors can beselectively modulated using compounds of this invention at rates setforth above for blocking the effects of agonists at 5-HT_(2B) receptors.The selective affinity may provide treatments with fewer side effectsand will facilitate the development of additional therapeutic agents.

Compounds exhibiting activity at the 5HT_(2B) receptor are useful fortreating disorders related to the modulation of the 5HT_(2B) receptor.For example, compounds having 5HT_(2B) antagonist activity reduce thespasticity of the colon. Thus, these compounds are useful for thetreatment of functional bowel disorders including irritable bowelsyndrome and irritable bowel syndrome-related symptoms. Theantispasmodic effect of such compounds can reduce abdominal painassociated with functional bowel disorders. Additionally, the 5HT_(2B)receptor is localized in other organs such as the brain, bladder, bloodvessels, stomach, and uterus, indicating that additional conditions are5HT_(2B) mediated.

Compounds demonstrating activity at the 5HT_(2A) receptor can beutilized in the treatment or prevention of conditions related tomodulation of the 5HT_(2A) receptor. Examples of such conditions includehypertension, sleep disorders, hallucinogenic activity, psychosis,anxiety, depression, thermoregulation, feeding disorders, andhypotension. Leonard, B. E., International Clinical Psychopharmacology,7, 13-21 (1992).

The term "receptor blocking dose", means an amount of compound necessaryto block a targeted receptor, selected from the group consisting of5-HT_(2A), 5-HT_(2B), and 5-HT_(1c) receptor in a mammal. The activecompounds are effective over a wide dosage range. For example, dosagesper day will normally fall within the range of about 0.05 to about 250mg/kg of body weight. In the treatment of adult humans, the range ofabout 0.5 to 100 mg/kg, in single or divided doses, is preferred. Theranges of about 5 mg/kg to about 60 mg/kg and about 10 mg/kg to about 50mg/kg are especially preferred. However, it will be understood that theamount of the compound actually administered will be determined by aphysician in light of the relevant circumstances, including thecondition to be treated, the choice of compound to be administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration, andtherefore the above dosage ranges are not intended to limit the scope ofthe invention in any way. The compounds may be administered by a varietyof routes such as oral, transdermal, subcutaneous, intranasal,intramuscular, and intravenous routes.

While it is possible to administer a compound of the invention directlywithout any formulation, the compounds are preferably employed in theform of a pharmaceutical formulation comprising a pharmaceuticallyacceptable excipient and at least one compound of the invention. Suchcompositions contain from about 0.1 percent by weight to about 90.0percent by weight of a present compound. As such, the present inventionalso provides pharmaceutical formulations comprising a compound of theinvention and a pharmaceutically acceptable excipient therefor.

In making the compositions of the present invention, the activeingredient is usually mixed with an excipient which can be a carrier, ora diluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Whenthe carrier serves as a diluent, it can be a solid, semi-solid, orliquid material which acts as a vehicle, excipient, or medium for theactive ingredient. Thus, the composition can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, emulsions,solutions, syrups, suspensions, aerosols (as a solid or in a liquidmedium), and soft and hard gelatin capsules.

The compounds of the invention may be delivered transdermally, ifdesired. Transdermal permeation enhancers and delivery systems,including patches and the like, are well known to the skilled artisan.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxy-benzoates, talc, magnesiumstearate, water, and mineral oil. The formulations may also includewetting agents, emulsifying and suspending agents, preserving agents,sweetening agents or flavoring agents. The formulations of the inventionmay be formulated so as to provide quick, sustained, or delayed releaseof the active ingredient after administration to the patient byemploying procedures well known in the art.

The compounds of this invention may be delivered transdermally usingknown transdermal delivery systems and excipients. Most preferrably, acompound of this invention is admixed with permeation enhancersincluding, but not limited to, propylene glycol, polyethylene glycolmonolaurate, and azacycloalkan-2-ones, and incorporated into a patch orsimilar delivery system. Additional excipients including gelling agents,emulsifiers, and buffers may be added to the transdermal formulation asdesired.

For oral administration, a compound of this invention ideally can beadmixed with carriers and diluents and molded into tablets or enclosedin gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, more usually about 5 toabout 300 mg, of the active ingredient. The term "unit dosage form"refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with a suitable pharmaceuticalcarrier.

The active compounds are effective over a wide dosage range. Forexample, dosages per day will normally fall within the range of about0.05 to about 250 mg/kg of body weight. In the treatment of adulthumans, the range of about 0.5 to 100 mg/kg, in single or divided doses,is preferred. The ranges of about 5 mg/kg to about 60 mg/kg and about 10mg/kg to about 50 mg/kg are especially preferred. However, it will beunderstood that the amount of the compound actually administered will bedetermined by a physician in light of the relevant circumstances,including the condition to be treated, the choice of compound to beadministered, the age, weight, and response of the individual patient,the severity of the patient's symptoms, and the chosen route ofadministration, and therefore the above dosage ranges are not intendedto limit the scope of the invention in any way. The compounds may beadministered by a variety of routes such as oral, transdermal,subcutaneous, intranasal, intramuscular, rectally, and intravenousroutes.

Pharmaceutical compositions of a compound of the present invention orits salts or solvates are most preferrably produced by formulating anactive compound in unit dosage form with a pharmaceutical carrier. Someexamples of unit dosage forms are tablets, pills, powders, aqueous andnon-aqueous oral solutions and suspensions, transdermal delivery devicesand patches, and parenteral solutions packaged in containers containingeither one or more unit dosages and may be capable of being subdividedinto individual doses. Some examples of suitable pharmaceutical carriersand/or diluents include gelatin capsules, sugars including lactose andsucrose, starches such as corn starch and potato starch, cellulosederivatives such as sodium carboxymethyl cellulose, ethyl cellulose,methyl cellulose, and cellulose acetate phthalate, gelatin, talc,stearic acid, magnesium stearate, vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma,propylene glycol, glycerin, sorbitol, polyethylene glycol, water, agar,alginic acid, isotonic saline, phosphate buffer solutions, lactic acid,glycolic acid, microcrystalline cellulose, kaolin, mannitol, dicalciumphosphate, sodium chloride, magnesium stearate, croscarmellose, alginicacid, sodium starch glycolate, lauryl sulfate. as well as othercompatible substances used in pharmaceutical formulations. The activecompound may be prepared as a microparticle using biodegradable polymersor other known methods. The composition may be prepared using knownformulation technology to provide a rapidly dissolving, sustainedrelease, or targeted delivery compositions. The compositions of thisinvnetion may contain other components such as coloring agents,flavoring, and/or preservatives. The compositions may contain othertherapeutic agents, for example an antacid or analgesic.

The article of manufacture will include packaging material. Packagingmaterial will preferably include a container. The preferred containerand packaging material can be selected using the characteristics of thecompound to be packaged. For example, the preferred container may beglass, plastic, foil, sealed bubble packaging, clear, amber, and mayincorporate other known pharmaceutical packaging technology. Thepackaging may include features such as cotton, silica or other dryingagents, and/or a measuring device. The article of manufacture shallinclude a label indicating that the composition is useful for thetreatment of an a condition associated with 5-HT_(2B) receptorstimulation malfunction. Most preferably, the condition is selected fromthe group consisting of urinary incontinence, bladder dysfunction,uterine dysfunction, cardiovascular disorder, and respiratory disorder.

In order to illustrate more fully the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as active compounds any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                                  Concentration                                                       Amount Per                                                                              by Weight                                                           Capsule   (percent)                                           ______________________________________                                        (+/-)6-ethyl-8-chloro-1-                                                                        250 mg      55.0                                             (3,4-dimethoxyphenyl)methyl!-                                                1,2,3,4-tetrahydro-9H-                                                        pyrido 3,4-b!indole                                                           hydrochloride                                                                 starch dried      200 mg      43.0                                            magnesium stearate                                                                               10 mg      2.0                                                               460 mg      100.0                                           ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

    ______________________________________                                                                Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                             ______________________________________                                        6-methyl-8-ethyl-1-                                                                             20 mg     10.0                                               (3-bromo-4-chloro-phenyl)-                                                   methyl)-1,2,3,4-tetrahydro-                                                   9H-pyrido 3,4b!indole                                                         (Z)-2-butenedioate                                                            starch            89 mg     44.5                                              microcrystalline  89 mg     44.5                                              cellulose                                                                     magnesium stearate                                                                               2 mg     1.0                                                                 200 mg    100.0                                             ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of medicament are made as follows:

    ______________________________________                                                                Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                             ______________________________________                                        5-fluoro-6-methyl-                                                                              100 mg    30.00                                             1-(1-(3-methylaminophenyl)-                                                   methyl)-1,2,3,4-                                                              tetrahydro-9H-pyrido-                                                          3,4-b!indole(Z)-2-                                                           butenedioate                                                                  polyoxyethylene    50 mg    0.02                                              sorbitan                                                                      monooleate                                                                    starch powder     250 mg    69.98                                                               400 mg    100.00                                            ______________________________________                                    

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets containing 10 mg of active ingredient are made as follows:

    ______________________________________                                                               Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                              ______________________________________                                        6-fluoro-8-phenoxy-                                                                            10 mg     10.0                                               1-(1-(4-ethoxy-phenyl)-                                                       methyl)-1,2,3,4-                                                              tetrahydro-9H-pyrido-                                                          3,4-b!indole(Z)-2-                                                           butenedioate                                                                  starch           45 mg     45.0                                               microcrystalline 35 mg     35.0                                               cellulose                                                                     polyvinylpyrrolidone                                                                            4 mg     4.0                                                (as 10% solution in                                                           water)                                                                        sodium carboxymethyl                                                                           4.5 mg    4.5                                                starch                                                                        magnesium stearate                                                                             0.5 mg    0.5                                                talc              1 mg     1.0                                                                 100 mg    100.0                                              ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formulation may be prepared using the ingredients below:

    ______________________________________                                                                  Concentration                                                       Amount Per                                                                              by Weight                                                           Capsule   (percent)                                           ______________________________________                                        5,6-difluoro-     250 mg      38.0                                            1-(1-(3-dimethylamino-phenyl)-                                                methyl)-1,2,3,4-                                                              tetrahydro-9H-pyrido-                                                          3,4-b!indole(Z)-2-                                                           butanedioate                                                                  microcrystalline  400 mg      60.0                                            cellulose                                                                     silicon dioxide    10 mg      1.5                                             fumed                                                                         stearic acid       5 mg       0.5                                                               665 mg      100.0                                           ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are asfollows:

    ______________________________________                                                          per 5 ml of                                                                   suspension                                                  ______________________________________                                        3-methyl-5-chloro-6-methyl-                                                                         5 mg                                                    1-(1-(3-dimethylamino-phenyl)-                                                methyl)-1,2,3,4-                                                              tetrahydro-9H-pyrido-                                                          3,4-b!indole(Z)-2-                                                           butenedioate                                                                  sodium carboxymethyl cellulose                                                                      50 mg                                                   syrup               1.25 ml                                                   benzoic acid solution                                                                             0.10 ml                                                   flavor              q.v.                                                      color               q.v.                                                      water               q.s. to 5 ml                                              ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

    ______________________________________                                                        Concentration by                                                              Weight (percent)                                              ______________________________________                                        5-propyl-6-ethyl- 0.25                                                        1- (3,4-dimethoxy-phenyl)-                                                    methyl)-1,2,3,4-                                                              tetrahydro-9H-pyrido-                                                          3,4-b!indole hydrochloride                                                   ethanol           29.75                                                       Propellant 22     70.00                                                       (chlorodifluoromethane)                                                                         100.00                                                      ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

Formulation 8

Injectables may be prepared as follows:

    ______________________________________                                                         Amount Per Batch                                             ______________________________________                                        6-(1-methylethyl)- 50 mg                                                      1,2,3,4-tetrahydro-1-                                                         (1-(4-dimethylaminophthalenyl)-                                               methyl)-9H-pyrido 3,4b!indole                                                 (Z)-2-butenedioate                                                            Devazepide for Injection                                                                         q.s.                                                       ______________________________________                                    

The compound or a suitable salt thereof is dissolved in, for example,ethanol, and passed through a 0.2 micron filter. Aliquots of filteredsolution are added to ampoules or vials, sealed and sterilized.

Formulation 9

Tablets containing 10 mg of active ingredient are made as follows:

    ______________________________________                                                              Concentration                                                         Amount Per                                                                            by Weight                                                             Tablet  (percent)                                               ______________________________________                                        7,8,9,10-tetrahydro-                                                                           6 g      2.0                                                 10-(1-(2-dimethyl-                                                            aminonaphthyleneyl)-                                                          methyl)-11H-benzo g!-                                                         pyrido 3,4-b!indole                                                           (Z)-2-butenedioate                                                            corn starch     200 g     78.0                                                microcrystalline                                                                               46 g     18.0                                                cellulose                                                                     Sterotex Powder HM                                                                             4 g      1.5                                                 Purified Water  300 mL                                                                        100 mg    100.0                                               ______________________________________                                    

The active ingredient, starch and cellulose are combined together in aplanetary mixer and mixed for 2 minutes. Water is added to thecombination and mixed for 1 minute. The resulting mix is spread on traysand dried in a hot air oven at 50° C. until a moisture level of 1 to 2percent is obtained. The dried mix then milled with a Fitzmill through a#RH2B screen, and added back to the milling mixture. The mixture is drumrolled for 5 minutes. Compressed tablets of 50 mg, 150 mg, and 200 mgare formed with appropriate sized punches.

Formulation 10

Capsules are prepared using the following ingredients:

    ______________________________________                                                                Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                             ______________________________________                                        (+/-)6-methyl-1-(1-(3-ethylamino                                                                200 mg    49.0                                              naphthalenyl)-1-ethyl)-                                                       1,2,3,4-tetrahydro-9H-                                                        pyrido 3,4-b!indole(Z)                                                        2-butenedioate                                                                lactose USP       200 mg    49.0                                              Serotex Powder     10 mg    2.0                                                                 410 mg    100.0                                             ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in410 mg quantities.

Formulation 11

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                               Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                              ______________________________________                                        Trans-9-methyl-5-(1-                                                                           250 mg    55.0                                               naphthylmethyl)-1,2,3,4-                                                      4a,5,6,10c,octahydrocyclo-                                                    penta a!pyrido 3,4-b!                                                         indole, hydrochloride                                                         starch dried     200 mg    43.0                                               magnesium stearate                                                                              10 mg    2.0                                                                 460 mg    100.0                                              ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 12

Capsules each containing 20 mg of medicament are made as follows:

    ______________________________________                                                                Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                             ______________________________________                                        spiro-6,6 2-(3,5-dimethoxy)-                                                                    20 mg     10.0                                              1,2,3,4-tetrahydronaphthyl!-                                                  10-methyl-2,3,4,4a,5,6,7,11a-                                                 octahydro-1H-indolo 2,3-c!-                                                   quinuclidine, hydrochloride                                                   starch            89 mg     44.5                                              microcrystalline  89 mg     44.5                                              cellulose                                                                     magnesium stearate                                                                               2 mg     1.0                                                                 200 mg    100.0                                             ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 13

Capsules each containing 100 mg of medicament are made as follows:

    ______________________________________                                                                Concentration                                                         Amount Per                                                                            by Weight                                                             Capsule (percent)                                             ______________________________________                                        spiro-6,6 2-(3-fluoro-4-                                                                        100 mg    30.00                                             methoxy)-1,2,3,4-                                                             tetrahydronaphthyl!-                                                          10-methyl-2,3,4,4a,5,6,7,11a-                                                 octahydro-1H-indolo 2,3-c!-                                                   quinuclidine, hydrochloride                                                   polyoxyethylene    50 mg    0.02                                              sorbitan                                                                      monooleate                                                                    starch powder     250 mg    69.98                                                               350 mg    100.00                                            ______________________________________                                    

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 14

Tablets containing 10 mg of active ingredient are made as follows:

    ______________________________________                                                               Concentration                                                         Amount Per                                                                            by Weight                                                             Tablet  (percent)                                              ______________________________________                                        8-fluoro-10-phenoxy-                                                                           10 mg     10.0                                               6-(1-naphthylmethyl)-                                                         2,3,4,4a,5,6,7,11c-                                                           octahydro-1H-indolo-                                                           2,3-c!quinoline, tartrate                                                    starch           45 mg     45.0                                               microcrystalline 35 mg     35.0                                               cellulose                                                                     polyvinylpyrrolidone                                                                            4 mg     4.0                                                (as 10% solution in                                                           water)                                                                        sodium carboxymethyl                                                                           4.5 mg    4.5                                                starch                                                                        magnesium stearate                                                                             0.5 mg    0.5                                                talc              1 mg     1.0                                                                 100 mg    100.0                                              ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 15

A tablet formulation may be prepared using the ingredients below:

    ______________________________________                                                              Concentration                                                         Amount Per                                                                            by Weight                                                             Tablet  (percent)                                               ______________________________________                                        8-methyl-10-methoxy-                                                                          250 mg    38.0                                                6-(1-naphthylethyl)-                                                          2,3,4,4a,5,6,7,11c-                                                           octahydro-1H-indolo-                                                           2,3-c!quinoline                                                              microcrystalline                                                                              400 mg    60.0                                                cellulose                                                                     silicon dioxide  10 mg    1.5                                                 fumed                                                                         stearic acid     5 mg     0.5                                                                 665 mg    100.0                                               ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 16

Suspensions each containing 5 mg of medicament per 5 ml dose are asfollows:

    ______________________________________                                                          per 5 ml of                                                                   suspension                                                  ______________________________________                                        8-chloro-10-cyclopropyl-                                                                            5 mg                                                    6-(1-naphthylethyl)-                                                          2,3,4,4a,5,6,7,11c-                                                           octahydro-1H-indolo-                                                           2,3-c!quinoline                                                              sodium carboxymethyl cellulose                                                                      50 mg                                                   syrup               1.25 ml                                                   benzoic acid solution                                                                             0.10 ml                                                   flavor              q.v.                                                      color               q.v.                                                      water               q.s. to 5 ml                                              ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 17

An aerosol solution is prepared containing the following components:

    ______________________________________                                                         Concentration by                                                              Weight (percent)                                             ______________________________________                                        spiro-6,6 2-(3-ethyl-4-ethoxy)-                                                                  0.25                                                       1,2,3,4-tetrahydronaphthyl!-                                                  10-methyl-2,3,4,4a,5,6,7,11a-                                                 octahydro-1H-indolo 2,3-c!-                                                   quinuclidine, maleate                                                         ethanol            29.75                                                      Propellant 22      70.00                                                      (chlorodifluoromethane)                                                                          100.00                                                     ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

Formulation 18

A tablet formulation may be prepared using the ingredients below:

    ______________________________________                                                                  Concentration                                                         Amount Per                                                                            by Weight                                                             Tablet  (percent)                                           ______________________________________                                        spiro-6,6 2-(3-ethyl-4-ethoxy)-                                                                   250 mg    38.0                                            1,2,3,4-tetrahydro-6-methyl-naphthyl!-                                        10-methyl-2,3,4,4a,5,6,7,11a-                                                 octahydro-1H-indolo 2,3-c!-                                                   quinuclidine, maleate                                                         microcrystalline    400 mg    60.0                                            cellulose                                                                     silicon dioxide      10 mg    1.5                                             fumed                                                                         stearic acid         5 mg     0.5                                                                 665 mg    100.0                                           ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

Compounds of the present invention were tested for 5-HT_(1C) receptoraffinity using the following procedure:

IA. Biological Reagent Preparation.

Beef brain was removed immediately after slaughter, and choroid plexuswere dissected over ice. Male Sprague-Dawley rats weighing 125-150 g(Harlan Industries, Cumberland, Ind.) were killed by decapitation. Thebrain of each was immediately removed and the cerebral cortex wasdissected over ice. Tissues were homogenized in 9 volumes of 0.32 mol/Lsucrose and centrifuged at 1,000×g for 10 minutes. The supernatant wascentrifuged at 17,000×g for 20 minutes. The pellet was suspended in 100volumes of 50 mM Tris-HCl (pH7.4), incubated at 37° C. for 10 minutesand centrifuged at 50,000×g for 10 minutes, and the process was repeatedthree times. The final pellets were frozen at -70° C. and used within 2weeks. Pellets were rehydrated with physiological buffer prior to use.

II. Assay Procedure.

Radioligand binding assays for 5-HT_(1c) and 5-HT₂ receptors wereconducted according to described methods. The assays can be conducted asdescribed by Hoyer D., Functional correlates of serotonin 5-HT₁recognition sites, J. Receptor Res 8, 59-81 (1988) and Hoyer D., EngelG., Kalkman H. O. Molecular pharmacology of 5-HT₁ and 5-HT₂ recognitionsites in rat and pig brain membranes: Radio-ligand binding studies with³ H!5-HT, ³ H!8-OH-DPAT, (-) ¹²⁵ I!iodocyanopindolol, ³ H!mesulergineand ³ H!ketanserin, Eur. J. Pharmacol, 118, 13-23 (1985).

For 5-HT_(1c) receptor assays increasing concentrations of experimentalcompound, 50 mM Tris HCl buffer pH 7.4, and tritiated mesulergine (2.0nM) (³ H ligand) were combined in polystyrene tubes at room temperature.The reaction was initiated by the addition of the resuspended choroidplexus tissue which had been preincubated at 37° C. for 20 minutes. Thereaction mixture was incubated in a 37° C. water bath for 15 minutes.

The reactions were terminated by rapid filtration, (Brandel CellHarvestor), through Whatman GF/B glass filters that had been presoakedin Tris buffer pH 7.4. The filters were then washed 2 times with 5 ml ofice cold Tris buffer pH 7.4. Washed filters were placed in scintillationvials and 10 ml RedySolv, (Brandel), was added and samples were countedin a Searle D-300 beta counter. Means and standard error statistics werecalculated for triplicate experimental determinations in certain cases.Mean values were obtained from three or more separate determinations.The incubation time for the reaction mixture was 15 minutes at 37° C.

Concentrations that caused a 50% inhibition of radioligand binding(IC₅₀) and Hill coefficient were obtained by computer-assistedregression analysis.

Radioligand Binding Studies:

Membrane preparation from transformed cells. Suspension cells expressingthe cloned rat 5-HT_(2B) receptor were harvested by centrifugation at2,200×g for 15 min at 4° C. Kursar, J. D., D. L. Nelson, D. B.Wainscott, M. L. Cohen, and M. Baez, Mol. Pharmacol. 42: 549-557 (1992).Membranes for the binding assays were prepared by vortexing the pelletin 50 mM Tris-HCl, pH 7.4 (0.5×10⁹ cells/30 ml). The,tissue suspensionwas then centrifuged at 39,800×g for 10 min at 4° C. This procedure wasrepeated for a total of three washes, with a 10 minute incubation at 37°C. between the first and second wash. The final pellet was homogenizedin 67 mM Tris-HCl, pH 7.4 (at 20-40 and 12.5 million cells/ml, originalcell number, for cells expressing low and relatively high levels of the5-HT_(2B) receptor, respectively) using a Tissumizer (Tekmar,Cincinnati, Ohio), setting 65 for 15 seconds.

³ H!5-HT binding studies. Binding assays were automated using a Biomek1000 (Beckman Instruments, Fullerton, Calif.) and were performed intriplicate in 0.8 ml total volume. Membrane suspension, 200 μl,(0.04-0.27 mg protein) and 200 μl of drug dilution in water were addedto 400 μl of 67 mM Tris-HCl, pH 7.4, containing ³ H!5-HT, pargyline,CaCl₂, and L-ascorbic acid. Final concentrations of pargyline, CaCl₂ andL-ascorbic acid were 10 μM, 3 mM and 0.1%, respectively. Tubes wereincubated at 37° C. for 15 min or at 0° C. for 2 hours (bindingequilibria were verified for both of these conditions), then rapidlyfiltered using a Brandel cell harvester (Model MB-48R; Brandel,Gaithersburg, Md.) through Whatman GF/B filters which had been presoakedin 0.5% polyethylenimine and precooled with ice-cold 50 mM Tris-HCl, pH7.4. The filters were then washed rapidly four times with one mlice-cold 50 mM Tris-HCl, pH 7.4. The amount of ³ H!5-HT trapped on thefilters was determined by liquid scintillation spectrometry (ReadyProtein) and automated using a Biomek 1000 (Beckman Instruments,Fullerton, Calif.) and were performed in triplicate in 0.8 ml totalvolume. Membrane suspension, 200 μl, (0.04-0.27 mg protein) and 200 μlof drug dilution in water were added to 400 μl of 67 mM Tris-HCl, pH7.4, containing ³ H!5-HT, pargyline, CaCl₂, and L-ascorbic acid. Finalconcentrations of pargyline, CaCl₂ and L-ascorbic acid were 10 μM, 3 mMand 0.1%, respectively. Tubes were incubated at 37° C. for 15 min or at0° C. for 2 hours (binding equilibria were verified for both of theseconditions), then rapidly filtered using a Brandel cell harvester (ModelMB-48R; Brandel, Gaithersburg, Md.) through Whatman GF/B filters whichhad been presoaked in 0.5% polyethylenimine and precooled with ice-cold50 mM Tris-HCl, pH 7.4. The filters were then washed rapidly four timeswith one ml ice-cold 50 mM Tris-HCl, pH 7.4. The amount of ³ H!5-HTtrapped on the filters was determined by liquid scintillationspectrometry (Ready Protein and Beckman) and determined for best fit toa one-site or a two-site binding model using a partial F-test. De Lean,A., A. A. Hancock, and R. J. Lefkowitz, Mol. Pharmacol. 21: 5-16 (1981).The following equation was used for a one-site binding model, ##EQU1##where Bound=amount of ³ H!5-HT specifically bound, B_(max) =maximumnumber of binding sites, K_(d) =equilibrium dissociation constant andL!=free concentration of ³ H!5-HT, or a two-site binding model, ##EQU2##where Bound=amount of ³ H!5-HT specifically bound, B_(max1) =maximumnumber of high affinity binding sites, B_(max2) =maximum number of lowaffinity binding sites, K_(d1) =equilibrium dissociation constant forthe high affinity site, K_(d2) =equilibrium dissociation constant forthe low affinity site and L!=free concentration of ³ H!5-HT. The IC₅₀values from the competition assays, the binding parameters for the IP₃standard curve and the EC₅₀ and E_(max) values from the IP₃ assays weredetermined by nonlinear regression analysis of four parameter logisticequations (Systat, Systat Inc, Evanston, Ill.). De Lean, A., A. A.Hancock, and R. J. Lefkowitz, Mol. Pharmacol. 21: 5-16 (1981). The IC₅₀values were converted to K_(i) values using the Cheng-Prusoff equation.Cheng, Y., and W. H. Prusoff, Biochem. Pharmacol. 22: 3099-3108 (1973).

Compounds of this invention were tested using substantially theprocedure describe in the Radioligand assay supra. and are summarized inTable I infra. The values in Table I are expressed as K_(i) valuescalculated as described supra. The blank values in Table I indicate thatthe compound was not tested in the corresponding assay.

                                      TABLE 1                                     __________________________________________________________________________                             5-HT.sub.2B Cells                                                                            5-HT.sub.2A                                                     3H!Serotonin   125I!DOI                                                      K.sub.i Rat                                                                            K.sub.i Human                                                                       K.sub.i Human                                                                       K.sub.i Rat                     STRUCTURE                5-HT.sub.2B                                                                            5-HT.sub.2B                                                                         5-HT.sub.2A                                                                         5-HT.sub.2A                     __________________________________________________________________________     ##STR75##               AVG. = 6.62 SEM = 0.09 N = 4                          ##STR76##               AVG. = 6.28 SEM = 0.91 N = 4                          ##STR77##               AVG. = 12.20 SEM = 1.54 N = 3                         ##STR78##               AVG. = 6.87 SEM = 0.55 N = 3                          ##STR79##               AVG. = 18.98 SEM = 7.56 N = 6                                                                = 0.90 = 0.32 = 5                                                                   = 5.12 = 1.21 = 5                ##STR80##               AVG. = 15.11 SEM = 2.43 N = 6                                                                = 15.09 = 2.26 = 5                                                                  = 2.05 = 0.29 = 5                ##STR81##               AVG. = 24.49 SEM = ? N = 2                            ##STR82##               AVG. = 35.13 SEM = ? N = 1                            ##STR83##               AVG. = 15.53 SEM = ? N = 1                            ##STR84##               AVG. = 10.24 SEM = 5.05 N = 4                                                                = 74.49 = 6.34 = 3                                                                  = 8.91 = 0.64 = 3                ##STR85##               AVG. = 11.36 SEM = 4.21 N = 4                                                                = 107.74 = 16.32 = 3                                                                = 12.44 = 2.29 = 3               ##STR86##               AVG. = 8.61 SEM = 4.21 N = 4                                                                 = 15.80 = 3.03 = 3                                                                  = 2.39 = 0.26 = 3                ##STR87##               AVG. = 9.35 SEM = 4.36 N = 4                                                                 = 18.60 = 2.42 = 3                                                                  = 2.44 = 0.35 = 3                ##STR88##               AVG. = 11.87 SEM = 1.93 N = 2                                                                = 32.71 = 0.84 = 2                     ##STR89##               AVG. = 4115.29 SEM = 311.55 N = 3                     ##STR90##               AVG. = 5153.15 SEM = ? N = 1                          ##STR91##               AVG. = 3019.67 SEM = ? N = 1                          ##STR92##               AVG. = 1501.95 SEM = ? N = 1                          ##STR93##               AVG. = 862.41 SEM = ? N = 1                           ##STR94##               AVG. = 936.34 SEM = ? N = 1                           ##STR95##               AVG. = 1752.56 SEM = ? N = 1                          ##STR96##               AVG. = 79.27 SEM = 5.39 N = 6                                                          = 215.15 = 4.97 = 2                                                                 = 6158.98 = 2084.19 = 2                ##STR97##               AVG. = 0.00 SEM = ? N = 1                                                              = 4749.52 = ? = 1                                                                   = 2229.48 = ? = 1                      ##STR98##               AVG. = SEM = N =                                                                       = 508.94 = 45.08 = 3                                                                = 354.03 = 41.34 = 3                   ##STR99##               AVG. = SEM = N =                                                                       = 784.17 = 32.35 = 3                                                                = 127.21 = 28.34 = 3                   ##STR100##              AVG. = SEM = N =                                                                       = 256.63 = 9.56 = 3                                                                 = 5690.86 = 560.80 = 3                 ##STR101##              AVG. = SEM = N =                                                                       = 1018.01 = ? = 1                                                                   = 6028.85 = ? = 1                      ##STR102##              AVG. = SEM = N =                                                                       = 1789.87 = ? = 1                                                                   = 0.00 = ? = 1                         ##STR103##              AVG. = 37.58 SEM = 4.76 N = 3                         ##STR104##              AVG. = 11.34 SEM = 2.24 N = 3                                                                = 33.67 = 2.01 = 3                                                                  = 14.22 = 2.36 = 3               ##STR105##              AVG. = 32.03 SEM = 3.49 N = 4                         ##STR106##              AVG. = 283.84 SEM = 13.48 N = 3                       ##STR107##              AVG. = 10.47 SEM = 1.46 N = 4                                                          = 11.91 = 1.09 = 3                           ##STR108##              AVG. = 130.79 SEM = 18.70 N = 4                       ##STR109##              AVG. = 10.19 SEM = 1.99 N = 6                                                          = 9.84 = 2.33 = 5                                                                   = 7.77 = 0.59 = 3                                                                   = 15.80 = 1.90 = 3               ##STR110##              AVG. = 9.15 SEM = 1.47 N = 3                          ##STR111##              AVG. = 146.84 SEM = 13.49 N = 7                                                        = 127.84 = 15.96 = 3                                                                = 120.16 = ? = 1                       ##STR112##              AVG. = 169.22 SEM = 50.27 N = 4                       ##STR113##              AVG. = 39.28 SEM = 14.04 N = 4                        ##STR114##              AVG. = 112.90 SEM = 5.61 N = 3                        ##STR115##              AVG. = 474.74 SEM = 80.54 N = 5                       ##STR116##              AVG. = 60.96 SEM = 16.54 N = 5                        ##STR117##              AVG. = 32.78 SEM = 4.99 N = 3                         ##STR118##              AVG. = 5.65 SEM = 0.55 N = 3                          ##STR119##              AVG. = 6.21 SEM = 0.55 N = 6                          ##STR120##              AVG. = 40.64 SEM = 4.45 N = 3                         ##STR121##              AVG. = 15.37 SEM = 1.67 N = 3                         ##STR122##              AVG. = 30.18 SEM = 0.90 N = 3                         ##STR123##              AVG. = 84.49 SEM = 8.44 N = 3                         ##STR124##              AVG. = 38.48 SEM = 3.77 N = 3                         ##STR125##              AVG. = 49.29 SEM = ? N = 1                            ##STR126##              AVG. = 6.52 SEM = 0.60 N = 2                          ##STR127##              AVG. = 49.92 SEM = 11.09 N = 2                        ##STR128##              AVG. = 41.62 SEM = 10.13 N = 2                        ##STR129##              AVG. = 4571.89 SEM = 499.67 N = 2                     ##STR130##              AVG. = 154.84 SEM = ? N = 1                           ##STR131##              AVG. = 20.85 SEM = 5.29 N = 2                         ##STR132##              AVG. = 62.43 SEM = 7.52 N = 3                         ##STR133##              AVG. = 102.06 SEM = 1.62 N = 2                        ##STR134##              AVG. = 14.78 SEM = ? N = 1                            ##STR135##              AVG. = 7.94 SEM = 0.52 N = 6                                                           = 11.21 = ? = 1                                                                     = 27.55 = 0.62 = 3                                                                  = 20.70 = 3.48 = 3               ##STR136##              AVG. = 336.55 SEM = ? N = 1                           ##STR137##              AVG. = 4.50 SEM = 0.47 N = 12                                                          = 3.79 = 0.80 = 8                            ##STR138##              AVG. = 3.58 SEM = 1.67 N = 3                          ##STR139##              AVG. = 3.17 SEM = 0.36 N = 3                                                                 = 21.74 = 0.74 = 3                                                                  = 15.74 = 1.41 = 3               ##STR140##              AVG. = 34.49 SEM = 2.85 N = 4                         ##STR141##              AVG. = 5.61 SEM = 0.91 N = 5                                                           = 1.40 = 0.08 = 5                                                                   = 44.46 = 0.75 = 3                     ##STR142##              AVG. = 30.07 SEM = 8.51 N = 5                                                          = 5.55 = 0.40 = 4                                                                   = 372.81 = 23.51 = 3                   ##STR143##              AVG. = 8.16 SEM = 2.16 N = 4                                                           = 1.50 = 0.35 = 4                                                                   = 23.39 = 3.81 = 3                     ##STR144##              AVG. = 3.10 SEM = 0.20 N = 3                                                           = 0.79 = 0.06 = 7                                                                   = 28.07 = 2.30 = 3                     ##STR145##              AVG. = 5.39 SEM = 0.68 N = 3                          ##STR146##              AVG. = 28.37 SEM = 2.08 N = 3                         ##STR147##              AVG. = 3.94 SEM = 0.88 N = 3                                                           = 1.29 = 0.12 = 3                                                                   = 5.62 = 0.63 = 3                      ##STR148##              AVG. = 39.70 SEM = 5.09 N = 3                         ##STR149##              AVG. = 1463.01 SEM = 110.95 N = 4                     ##STR150##              AVG. = 14.18 SEM = 1.74 N = 4                         ##STR151##              AVG. = 44.91 SEM = 1.48 N = 3                         ##STR152##              AVG. = 5.02 SEM = 0.51 N = 3                                                           = 1.64 = 0.23 = 4                                                                   = 0.83 = 0.10 = 3                      ##STR153##              AVG. = 4.82 SEM = 0.23 N = 3                          ##STR154##              AVG. = 2.16 SEM = 0.33 N = 3                          ##STR155##              AVG. = 228.87 SEM = 18.34 N = 3                       ##STR156##              AVG. = 6.42 SEM = 0.78 N = 3                                                           = 2.01 = ? = 1                                                                      = 23.08 = ? = 1                        ##STR157##              AVG. = 4.38 SEM = 1.25 N = 3                          ##STR158##              AVG. = 3.31 SEM = 0.31 N = 3                                                           = 0.74 = 0.04 = 3                                                                   = 4.63 = 0.26 = 3                      ##STR159##              AVG. = 219.79 SEM = 20.68 N = 3                       ##STR160##              AVG. = 4609.36 SEM = 316.40 N = 3                     ##STR161##              AVG. = 379.15 SEM = 16.72 N = 3                       ##STR162##              AVG. = 114.16 SEM = 7.17 N = 3                        ##STR163##              AVG. = 404.85 SEM = 51.64 N = 3                       ##STR164##              AVG. = 97.53 SEM = ? N = 1                            ##STR165##              AVG. = 71.75 SEM = ? N = 1                            ##STR166##              AVG. = 70.71 SEM = 10.08 N = 3                        ##STR167##              AVG. = 15.83 SEM = 1.73 N = 3                         ##STR168##              AVG. = 13.98 SEM = 1.00 N = 3                                                          = 16.43 = ? = 1                                                                     = 41.71 = 7.42 = 4                                                                  = 47.00 = 5.15 = 3               ##STR169##              AVG. = 6.20 SEM = 0.62 N = 3                                                           = 9.68 = 1.12 = 3                                                                   = 22.72 = 2.15 = 6                                                                  = 25.61 = 3.43 = 3               ##STR170##              AVG. = 62.09 SEM = 1.76 N = 3                         ##STR171##              AVG. = 57.89 SEM = 7.60 N = 3                         ##STR172##              AVG. = 32.44 SEM = 3.48 N = 3                         ##STR173##              AVG. = 322.26 SEM = 35.50 N = 3                       ##STR174##              AVG. = 25.63 SEM = 2.59 N = 3                         ##STR175##              AVG. = 78.46 SEM = 1.22 N = 2                         ##STR176##              AVG. = 60.10 SEM = 2.07 N = 3                         ##STR177##              AVG. = 2.69 SEM = 0.24 N = 6                                                           = 2.68 = 0.24 = 4                                                                   = 20.61 = 1.28 = 4                                                                  = 15.49 = 0.79 = 3               ##STR178##              AVG. = 3.19 SEM = 0.33 N = 3                                                           = 0.84 = 0.15 = 4                                                                   = 0.93 = 0.07 = 3                      ##STR179##              AVG. = 8.77 SEM = ? N = 1                             ##STR180##              AVG. = 5652.17 SEM = ? N = 1                          ##STR181##              AVG. = 15.26 SEM = ? N = 1                                                             = 10.15 = 2.19 = 4                                                                  = 17.76 = 0.68 = 3                     ##STR182##              AVG. = SEM = N =                                                                       = 1.69 = ? = 1                                                                      = 49.70 = ? = 1                        ##STR183##              AVG. = SEM = N =                                                                       = 2.08 = ? = 1                                                                      = 6.71 = ? = 1                         ##STR184##              AVG. = SEM = N =                                                                       = 0.37 = ? = 1                                                                      = 12.23 = ? = 1                        ##STR185##              AVG. = SEM = N =                                                                       = 0.87 = ? = 1                                                                      = 17.48 = ? = 1                        ##STR186##              AVG. = SEM = N =                                                                       = 1.47 = ? = 1                                                                      = 54.85 = ? = |                        ##STR187##              AVG. = SEM = N =                                                                       = 3.46 = ? = 1                                                                      = 201.26 = ? = 1                       ##STR188##              AVG. = 44.65 SEM = 25.15 N = 5                                                         = 12.44 = 1.70 = 3                                                                  = 1.25 = 0.56 = 5                                                                   = 5.36 = 1.85 = 5                ##STR189##              AVG. = 22.29 SEM = 6.65 N = 5                                                          = 4.30 = 0.30 = 3                                                                   = 11.33 = 3.26 = 5                                                                  = 1.57 = 0.49 = 5                ##STR190##              AVG. = 30.90 SEM = 4.52 N = 3                                                          = 6.24 = 0.29 = 3                                                                   = 21.18 = 3.78 = 3                                                                  = 2.82 = 0.40 = 3                ##STR191##              AVG. = SEM = N =                                                                       = 7.87 = -- = 1                                                                     = 0.60 = -- = 1                        ##STR192##              AVG. = SEM = N =                                                                       = 2.24 = -- = 1                                                                     = 21.92 = -- = 1                      __________________________________________________________________________    The following Cell assays use Human Cells                                     Compound    5HT.sub.2B Cells 5HT.sub.2A Cells                                                                    5HT.sub.2C Cells                           __________________________________________________________________________    Example 100 16.44            292.58                                                                              351.96                                     Example 105 22.07            86.48 195.44                                     Example 102 168.49           917.16                                                                              2172.86                                    Example 106 367.41           263.94                                                                              1108.87                                    Example 104 11.35            32.99 52.06                                      Example 97  9.56             123.93                                                                              220.51                                     Example 99  106.17           556.40                                                                              1117.00                                    Example 107 177.89           362.79                                                                              325.10                                     Isomer 107(1)                                                                             142.80           152.65                                                                              137.76                                     Isomer 107(2)                                                                             2894.33          1967.05                                                                             6211.80                                    Example 101 121.19           172.03                                                                              783.35                                     Example 98  52.54            53.65 202.60                                     Example 96  667.82           277.62                                                                              976.73                                     Example 95  839.63           3443.51                                                                             2641.21                                    Example 103 3520.31          1447.65                                                                             9247.06                                    __________________________________________________________________________

Assay Methods 5-HT_(2B) receptor in tissue in vitro:

Male Wistar rats (150-375 g; Laboratory Supply, Indianapolis, Ind.) weresacrificed by cervical dislocation, and longitudinal section of thestomach fundus were prepared for in vitro examination. Four preparationswere obtained from one rat fundus. Cohen, M. L. and J. Pharmacol. Exp.Ther. 233:75-79 (1985). Tissues were mounted in organ baths containing10 mL of modified Krebs' solution of the following composition(millimolar concentrations): NaCl, 118.2, KCl, 4.6; CaCl₂.H₂ O, 1.6; KH₂PO₄, 1.2; MgSO₄, 1.2; dextrose, 10.0; and NaHCO₃, 24.8. Tissue bathsolutions were maintained at 37° C. and equilibrated with 95% O₂ and 5%CO₂. Tissues were placed under optimum resting force (4 g) and wereallowed to eguilibrate for approximately 1 hour before exposure to thetest compound. Isometric contractions were recorded as changes in gramsof force on a Beckman Dynograph with Statham UC-3 transducers.

Determination of Apparent Antagonist Dissociation Constant:

Noncumulative contractile concentration-response curves for serotoninand other agonists in the fundus were obtained by a stepwise increase inconcentration after washing out the preceding concentrations every 15-20minutes. Each agonist concentration remained in contact with the tissuefor approximately 2 minutes and maximum response to each compoundconcentration was measured ED₅₀ values were taken as the concentrationof agonist that produced half-maximal contraction. After controlresponses were obtained, tissues were incubated with an appropriateconcentration of buffer or antagonist for 1 hour. Responses to serotoninwere then repeated in the presence of an antagonist. Concentrationresponses utilized only one agonist and one antagonist concentration pertissue. In general, successive agonist responses in the presence ofbuffer treatment were unaltered (average dose ratio was 1.28±0.21).

Apparent antagonist dissociation constants (K_(B)) were determined foreach concentration of antagonist according to the following equation:

    K.sub.B = B!/(dose ratio-1)

where B! is the concentration of the antagonist and dose ratio is theED₅₀ of the agonist in the presence of the antagonist divided by thecontrol ED₅₀. Generally, parallel shifts in the concentration-responsecurves occurred in the presence of antagonists. The results wereexpressed as the negative logarithm of the K_(B) (i.e., -log K_(B)).Calculations were completed using known methods.

The results of the in vitro assay for certain compounds of thisinvention are presented in Table II. The values in Table II areexpressed as -log K_(B) ±standard error (number of data points). The5-HT_(2B) value represents the negative log of the concentration of anantagonist that will produce a two fold dextral shift in theconcentration response curve to serotonin in the rat stomach funduswhich is mediated by 5-HT_(2B) receptors. Likewise, the 5-HT_(2A) valuerepresents the negative log of the concentration of an antagonist thatwill produce a two fold dextral shift in the concentration responsecurve to serotonin in the rat jugular vein which is mediated by5-HT_(2A) receptors. The blank values in Table II indicate that thecompound was not tested in the indicated assay.

                  TABLE II                                                        ______________________________________                                                    5-HT.sub.2B   5-HT.sub.2A                                         Example #   (Fundus)      (Jugular)                                           ______________________________________                                        1           9.00 ± 0.07 (3)                                                3           8.78 ± 0.24 (4)                                                4           8.92 ± 0.29 (4)                                                5                                                                             6           9.60 ± 0.13 (7)                                                7           9.02 ± 0.35 (3)                                                8           8.45 ± 0.24 (3)                                                9           9.30 ± 0.12 (7)                                                10          9.22 ± 0.05 (3)                                                11          <7.52 (4)                                                         12          9.29 ± 0.18 (4)                                                13          8.50 ± 0.13 (4)                                                14          9.61 ± 0.22 (5)                                                15          9.34 ± 0.12 (3)                                                16          9.71 ± 0.14 (6)                                                                          8.15 ± 0.28 (3)                                  17          9.46 ± 0.11 (6)                                                                          7.66 ± 0.13 (4)                                  18          8.80 ± 0.17 (3)                                                19          10.12 ± 0.18 (3)                                               20          9.48 ± 0.30 (4)                                                                          7.21 ± 0.20 (4)                                  21                                                                            22          8.21 ± 0.43 (3)                                                23                                                                            24                                                                            25                                                                            26                                                                            27                                                                            28          8.55 ± 0.10 (4)                                                29          8.12 ± 0.16 (7)                                                30          8.89 ± 0.12 (4)                                                31          8.95 ± 0.17 (3)                                                                          7.29 ± 0.09 (4)                                  32                                                                            33                                                                            34          9.42 ± 0.18 (5)                                                35          *9.06 ± 0.27 (3)                                               36          9.80 ± 0.15 (4)                                                                          8.14 ± 0.10 (6)                                  37          9.19 ± 0.14 (4)                                                38                                                                            39          8.32 ± 0.17 (3)                                                40          9.75 ± 0.11 (6)                                                41          9.81 ± 0.18 (3)                                                                          7.94 ± 0.15 (6)                                  42          9.56 ± 0.22 (3)                                                43          9.44 ± 0.16 (6)                                                44          8.40 ± 0.40 (3)                                                45          8.14 ± 0.32 (3)                                                46          9.37 ± 0.11 (8)                                                                          8.22 ± 0.07 (12)                                 47                                                                            48          **                                                                49          *10.41 ± 0.22 (5)                                              50          8.40 ± 0.28 (3)                                                51          9.75 ± 0.11 (8)                                                                          8.07 ± 0.10 (8)                                  52          *9.10 ± 0.28 (3)                                               53          **                                                                54          **                                                                55          8.95 ± 0.07 (4)                                                56          *7.53 ± 1.08 (4)                                               57          <8.0 (3)                                                          58          <7.52 (4)                                                         59          9.69 ± 0.21 (7)                                                60          8.92 ± 0.04 (4)                                                61          8.44 ± 0.22 (4)                                                62          8.58 ± 0.23 (3)                                                63          9.09 ± 0.23 (3)                                                64          9.73 ± 0.05 (3)                                                ______________________________________                                         *Approximate value                                                            **Noncompetitive inhibitors at 30 nM                                     

Functional In vitro assay:

Sprague-Dawley rats (200-250 g; Laboratory Supply, Indianapolis, Ind.)were sacrificed by cervical dislocation and 8 cm segment of distal colonwas removed and washed in ice cold modified Kreb's solution of thefollowing composition (millimolar): Nacl, 118.2; Kcl, 4.6; Cacl₂. H₂ O,1.6; KH₂ PO₄, 1.2; MgSO₄, 1.2; dextrose, 10.0; and NaHCO₃, 24.8. Thecolon was mounted on a glass rod and the longitudinal muscle layer withattached myenteric plexi was removed and mounted in organ baths,containing above described Kreb's solution maintained at 37° C. andequilibrated with 95% O₂ and 5% CO₂. Tissues were placed under 2 gtension and allowed to stabilize for 1 hour. Isometric contractions wererecorded as changes in grams of force using grass FT03 transducers andMI² -computerized dynograph system. Cumulative concentration-responsecurves for serotonin were obtained by a stepwise increase inconcentration after washing out the preceding concentration for 10-15minutes. Each agonist concentration remained in contact with the tissuefor 5 minutes. Maximum response to each concentration was determined anddigitized. EC₅₀ values were taken as the concentration of agonist thatproduced half maximal contraction. After control responses wereobtained, tissues were incubated with an appropriate concentration ofantagonist for 15 minutes. Response to serotonin were then repeated inthe presence of an antagonist. Concentration-response utilized only oneconcentration of antagonist per tissue. Apparent antagonist dissociationconstants (K_(B)) were determined for each concentration of antagonistaccording to the following equation:

    K.sub.B = B!/(dose ratio-1),

where B! is the concentration of the antagonist and dose ratio is theED₅₀ of the agonist in the presence of antagonist divided by the controlED₅₀. The results were expressed as the negative logarithm of the K_(B)(i.e., -log K_(B)) (Br. J. Pharmacol. Methods 4:4165, (1980).

The functional in vitro method described supra. was used to testcompounds of this invention. Results obtained using the functional invitro assay are presented in Table III. Values are expressed as pK_(i)and pA₂ (-log K_(B)). The following table illustrates the resultsobtained when the compounds were tested using the Radioligand assaysupra. (pKi) and the functional in vitro method described supra. (pA₂)

                  TABLE III                                                       ______________________________________                                        Compound             pKi    pA.sub.2                                          ______________________________________                                        Example 73           7.85   8.9                                               Example 49           8.4    8.2                                               Example 20           8.51   7.8                                               Example 72           7.8    7.5                                               Example 41           8.19   7.2                                               Example 17           8.09   6.2                                               Example 22           8.27   4.8                                               7-methyl-8-chloro-1,2,3,4-                                                                         8.57   8.3                                               tetrahydro-9H-pyrido 3,4b!-                                                   indole                                                                        6-bromo-1,2,3,4-tetrahydro-                                                                        7.21   8.2                                               9H-pyrido 3,4b!-indole                                                        6-chloro-1,2,3,4-tetrahydro-                                                                       7.15   7.2                                               9H-pyrido 3,4b!-indole                                                        ______________________________________                                    

In vivo Studies:

Sprague-Dawley Rats (250-300 g) were fasted overnight. The rats wereanesthetized with urethane (250 mg) delivered intraperitoneally. Theabdominal cavity was opened and strain guage transducers were sewn onthe antimesenteric border of the colon. The transducers were oriented torecord circular muscle contractions. The animal body temperature wasmaintained by a heating pad. An intravenous catheter was inserted intothe jugular vein for drug administration. The carotid blood pressure wasalso monitored. Output of the strain guage transducers was graphed on aBeckman Dynograph. Baseline motility was monitored for 30 minutes. Atthe end of the 30 minute period, a vehicle control dose was administeredand motility was recorded for an additional 15 minutes. A serotonin doseresponse was developed. Successively higher doses of serotonin wereadministered at 15 minute intervals. An ED₅₀ dose was calculated, whichwas the dose producing half maximal contraction. In antagonistexperiments, historical ED₅₀ dose was administered to validate theexperimental set up. Next, a dose of antagonist was given. The motilitywas monitored for 15 minutes. After the 15 minute monitoring, an ED₅₀dose was administered. Motility was evaluated by measuring the number ofcontractions and multiplying them by the amplitude of contractions overa set time period to provide a Motility Index. The percent inhibitionwas calculated from the vehicle (no antagonist) treated group. A minimumof three rats were used for each concentration and data from differentanimals was pooled to determine ED₅₀ values.

Compounds of this invention proved to be active using the in vivo methoddescribed supra. For example, the compound of Example 73 produced anED₅₀ value of 3.2 mg/kg, i.v.

We claim:
 1. A method for treating a mammal suffering from orsusceptible to a condition associated with abnormal or dysfunctional5-HT_(2B) receptor stimulation, comprising administering to the mammalan effective amount of a compound of the Formula ##STR193## wherein R₈is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo, halo(C₂ -C₆)alkyl,halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁ -C₆alkyl)_(m) amino, NO₂, --SR₅, OR₅, C₃ -C₈ cycloalkyl, substituted C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl,substituted C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, orC₇ -C₂₀ arylalkyl;R₅ is hydrogen or C₁ -C₄ alkyl; R_(5') is C₁ -C₄alkyl; m is 1 or 2; R₉ and R₁₀ independently are hydrogen, C₁ -C₆ alkyl,C₃ -C₈ cycloalkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, or C₇ -C₂₀ arylalkyl; R₁₁is C₁ -C₄ alkyl, OR_(5'), fluoro, bromo, iodo, or chloro; and R_(12') ishydrogen or C₁ -C₄ alkyl; ora pharmaceutically acceptable salt orsolvate thereof.
 2. The method of claim 1 wherein the compound is a5-HT_(2B) receptor antagonist.
 3. A method of claim 1 wherein thecondition is urinary incontinence, bladder dysfunction, uterinedysfunction, a cardiovascular disorder, or a respiratory disorder.
 4. Amethod of claim 3 wherein the condition is a cardiovascular disorder. 5.A method of claim 3 wherein the condition is a bladder dysfunction orurinary incontinence.
 6. A method of claim 3 wherein the condition is arespiratory disorder.
 7. The method of claim 1 wherein the condition ismigraine headache.
 8. A method for treating a mammal suffering from orsusceptible to a Functional Bowel Disorder associated with abnormal ordysfunctional 5-HT_(2B) receptor stimulation, comprising administeringto the mammal an effective amount of a compound of the Formula##STR194## wherein R₈ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo,halo(C₂ -C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅, C₃ -C₈ cycloalkyl,substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁-C₃)alkyl, or C₇ -C₂₀ arylalkyl;R₅ is hydrogen or C₁ -C₄ alkyl; R_(5')is C₁ -C₄ alkyl; m is 1 or 2; R₉ and R₁₀ independently are hydrogen, C₁-C₆ alkyl, C₃ -C₈ cycloalkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, or C₇ -C₂₀arylalkyl; R₁₁ is C₁ -C₄ alkyl, OR_(5'), fluoro, bromo, iodo, or chloro;and R_(12') is hydrogen or C₁ -C₄ alkyl; ora pharmaceutically acceptablesalt or solvate thereof.
 9. The method of claim 8 wherein the FunctionalBowel Disorder is Irritable Bowel Syndrome, ichlasia, hypertonic loweresophpageal sphincter, tachygastria, hypermotility associated withirritable bowel syndrome, or constipation.
 10. A method for blocking a5-HT_(2B) receptor in a mammal comprising administering to the mammal a5-HT_(2B) receptor-blocking dose of a compound of the Formula ##STR195##wherein R₈ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo, halo(C₂-C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁-C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅, C₃ -C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl,substituted C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, orC₇ -C₂₀ arylalkyl;R₅ is hydrogen or C₁ -C₄ alkyl; R_(5') is C₁ -C₄alkyl; m is 1 or 2; R₉ and R₁₀ independently are hydrogen, C₁ -C₆ alkyl,C₃ -C₈ cycloalkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, or C₇ -C₂₀ arylalkyl; R₁₁is C₁ -C₄ alkyl, OR_(5'), fluoro, bromo, iodo, or chloro; and R_(12') ishydrogen or C₁ -C₄ alkyl; ora pharmaceutically acceptable salt orsolvate thereof.
 11. The method of claim 10 wherein the mammal is ahuman.
 12. A method for selectively blocking a 5-HT_(2B) receptor in amammal comprising administering to the mammal a 5-HT_(2B) selectivecompound of the Formula ##STR196## wherein R₈ is hydrogen, C₁ -C₆ alkyl,C₂ -C₆ alkenyl, halo, halo(C₂ -C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁-C₁₀ alkanoyl, CO₂ R_(5'), (C₁ -C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅, C₃-C₈ cycloalkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl, substituted C₅ -C₈ cycloalkenyl, C₅ -C₈cycloalkenyl-(C₁ -C₃)alkyl, or C₇ -C₂₀ arylalkyl;R₅ is hydrogen or C₁-C₄ alkyl; R_(5') is C₁ -C₄ alkyl; m is 1 or 2; R₉ and R₁₀ independentlyare hydrogen, C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, substituted C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁-C₃)alkyl, or C₇ -C₂₀ arylalkyl; R₁₁ is C₁ -C₄ alkyl, OR_(5'), fluoro,bromo, iodo, or chloro; and R_(12') is hydrogen or C₁ -C₄ alkyl; orapharmaceutically acceptable salt or solvate thereof.
 13. An article ofmanufacture comprising a pharmaceutical agent of the Formula ##STR197##wherein R₈ is hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, halo, halo(C₂-C₆)alkyl, halo(C₂ -C₆)alkenyl, COR₅, C₁ -C₁₀ alkanoyl, CO₂ R_(5'), (C₁-C₆ alkyl)_(m) amino, NO₂, --SR₅, OR₅, C₃ -C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁ -C₃)alkyl, C₅ -C₈ cycloalkenyl,substituted C₅ -C₈ cycloalkenyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, orC₇ -C₂₀ arylalkyl;R₅ is hydrogen or C₁ -C₄ alkyl; R_(5') is C₁ -C₄alkyl; m is 1 or 2; R₉ and R₁₀ independently are hydrogen, C₁ -C₆ alkyl,C₃ -C₈ cycloalkyl, substituted C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl-(C₁-C₃)alkyl, C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl, or C₇ -C₂₀ arylalkyl; R₁₁is C₁ -C₄ alkyl, OR_(5'), fluoro, bromo, iodo, or chloro; and R_(12') ishydrogen or C₁ -C₄ alkyl;or a pharmaceutically acceptable salt orsolvate thereof, contained within a packaging material that has a labelindicating that the pharmaceutical agent can be used for treating acondition associated with dysfunctional or abnormal 5-HT_(2B) receptorstimulation.